Glycyrrhizic acid ameliorates the kynurenine pathway in association with its antidepressant effect

Wang, Bo; Lian, Yong‐Jie; Dong, Xin; Wei, Peng; Liu, Linlin; Su, Wen‐Jun; Gong, Hongyun; Zhang, Ting; Jiang, Chun‐Lei; Li, Jiasi; Wang, Yunxia

doi:10.1016/j.bbr.2018.01.024

Cited by 47 publications

(38 citation statements)

References 55 publications

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“…In our present study, the alterations of microglia and astrocytes in the brain were different. The expression of microglia maker Iba1 was increased in hippocampus and mPFC, being consistent with other reports of the proliferation and activation of microglia in hippocampus and PFC in unpredictable stress animal models (Kreisel et al, 2014 ; Pan et al, 2014 ; Wang B. et al, 2018 ). Further investigation confirmed that the activated microglia in depression mouse model were mainly M1-like polarized, which was characterized by abundant expression of iNOS and pro-inflammatory cytokines.…”

Section: Discussionsupporting

confidence: 91%

Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

Zhang

Jiang

et al. 2018

Front. Cell. Neurosci.

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Backgrounds: Abundant reports indicate that neuroinflammatory signaling contributes to behavioral complications associated with depression and may be related to treatment response. The glial cells, especially microglia and astrocytes in brain regions of hippocampus and medial prefrontal cortex (mPFC), are major components of CNS innate immunity. Moreover, purinergic receptor P2X, ligand-gated ion channel 7 (P2X7R) was recently reckoned as a pivotal regulator in central immune system. Besides, it was pointed out that clemastine, a first-generation histamine receptor H1 (HRH1) antagonist with considerable safety profile and pharmacological effect, may suppress immune activation through modulating P2X7R. Herein, we investigated the potential anti-neuroinflammatory effects of clemastine on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in a mouse model.Methods: Male BALB/c mice were subjected to CUMS for 4 weeks, some of them were injected with clemastine fumarate solution. After the stress procedure, behavioral tests including Sucrose Preference Tests (SPTs), Tail Suspension Tests (TSTs) and locomotor activities were performed to evaluate depressive-like phenotype. Subsequently, expression of cytokines and microglia-related inflammatory biomarkers were assessed.Results: In the present research, we found that clemastine significantly reversed both the declination of SPT percentage and the extension of TST immobility durations in depression mouse model without affecting locomotor activity. Also, we observed that clemastine regulated the imbalance of pro-inflammatory cytokines including interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in the hippocampus and serum of depressive-like mice. Additionally, clemastine significantly suppressed microglial M1-like activation specifically in the hippocampus, and also improved hippocampal astrocytic loss. Furthermore, clemastine downregulated hippocampal P2X7R without interfering with the expression of HRH1.Conclusion: As a safe and efficient anti-allergic agent, clemastine could impressively alleviate stress-related depressive-like phenotype in mice. Further evidence supported that it was because of the potential function of clemastine in modulating the expression of P2X7 receptor possibly independent of HRH1, therefore suppressing the microglial M1-like activation and pro-inflammatory cytokines release in brain regions of hippocampus rather than mPFC.

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Section: Discussionsupporting

confidence: 91%

Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

Zhang

Jiang

et al. 2018

Front. Cell. Neurosci.

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“…Consistent with a previous report ( 68 ), we observed increased TRP turnover in the CUMS rats in this study, which increased the accumulation of KYN and further increased the production of several neurotoxic metabolites such as 3-HK (Figure 4I ). In addition, NaP administration reduced the turnover of TRP by decreasing the production of KYN and its neurotoxic metabolites, which is consistent with the reported antidepressant effects of glycyrrhizic acid ( 69 ) and ketamine ( 70 ).…”

Section: Discussionsupporting

confidence: 86%

Short Term Intrarectal Administration of Sodium Propionate Induces Antidepressant-Like Effects in Rats Exposed to Chronic Unpredictable Mild Stress

Hou

Wang

et al. 2018

Front. Psychiatry

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Depression has been correlated with metabolic disorders, and the gut microbiota and its metabolites have been reported to be key factors affecting metabolic disorders. Several metabolites generated by the gut microbiota have been reported to exert antidepressant-like effects, including the short chain fatty acid (SCFA) butyrate. However, recent work has suggested that the abundance of butyrate is not significantly changed in neither human nor experimental animals with depression, and butyrate has been reported to decrease upon the administration of prebiotics with antidepressant-like effects. Supplementation of endogenous metabolites that are unchanged in depression may induce additional metabolic disorders and may lead to poorer clinical outcomes. However, the endogenous metabolites that are imbalanced in depression may include several antidepressant candidates that could circumvent these problems. In this study, we used GC-MS spectrometry to study the fecal metabolome of rats under Chronic Unpredictable Mild Stress (CUMS). We carried out static and dynamic metabolomics analyses to identify the differential metabolites between the CUMS rats and control rats. We identified propionic acid, rather than butyric acid, as a differential metabolite of the CUMS rats. Consistent with this, a 1-week intrarectal administration of sodium propionate (NaP, the salt form of propionic acid) induced antidepressant-like effects and partially rebalanced the plasma metabolome. The antidepressant-like effects of NaP were correlated with differential rescue of neurotransmitters in the prefrontal cortex, which may be achieved through the reduction of catabolism of noradrenaline, tryptophan and dopamine, rather than serotonin. These findings support NaP as a potential candidate in fighting depression by administering an endogenous metabolite.

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“…Indoleamine 2,3-dioxygenase-1 is the first and rate-limiting enzyme responsible for converting TRP to KYN outside of the liver. We found that IDO1 levels increased after CMS, which suggested IDO1 is an immune mediator in MDD pathogenesis ( Murakami and Saito, 2013 ; Wang et al, 2018 ). IDO1 activity can be directly inhibited by reactive oxygen species ( Marin et al, 2017 ) or activated by several pro-inflammatory cytokines, including IFNs (IFN-α, -β, and -γ), TNF-α, and IL-6 ( Galley et al, 2014 ).…”

Section: Discussionmentioning

confidence: 66%

“…IDO1 is an immune mediator that is responsive to several proinflammatory mediators, including IFNs (IFN-α, -β, and -γ), TNF-α, and IL-6 ( Murakami and Saito, 2013 ). Increased IDO1 activity has been found to be positively correlated with the severity of depressive scores, and could predict future risk for developing stress-related symptoms ( Murakami and Saito, 2013 ; Wang et al, 2018 ), which due to systemic immune activation, drives TRP down the IDO1-mediated KYN pathway. Previous studies have found potential antidepressant efficacy by blocking IDO1 activity both in chronic stress- and inflammation-induced behavior models ( Laugeray et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis

Wang

et al. 2018

Front. Behav. Neurosci.

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In recent years, a burgeoning body of research has revealed links between depression and the gut microbiota, leading to the therapeutic use of probiotics for stress-related disorders. In this study, we explored the potential antidepressant efficacy of a multi-strain probiotics treatment (Lactobacillus helveticus R0052, Lactobacillus plantarum R1012, and Bifidobacterium longum R0175) in a chronic mild stress (CMS) mouse model of depression and determined its probable mechanism of action. Our findings revealed that mice subjected to CMS exhibited anxiety- and depressive-like behaviors in the sucrose preference test, elevated plus maze, and forced swim test, along with increased interferon-γ, tumor necrosis factor-α, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. Moreover, the microbiota distinctly changed from the non-stress group and was characterized by highly diverse bacterial communities associated with significant reductions in Lactobacillus species. Probiotics attenuated CMS-induced anxiety- and depressive-like behaviors, significantly increased Lactobacillus abundance, and reversed the CMS-induced immune changes in the hippocampus. Thus, the possible mechanism involved in the antidepressant-like activity of probiotics is correlated with Lactobacillus species via the gut microbiota-inflammation-brain axis.

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Glycyrrhizic acid ameliorates the kynurenine pathway in association with its antidepressant effect

Cited by 47 publications

References 55 publications

Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

Short Term Intrarectal Administration of Sodium Propionate Induces Antidepressant-Like Effects in Rats Exposed to Chronic Unpredictable Mild Stress

Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis

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