Inhibition of the NLRP3 inflammasome with MCC950 prevents chronic social isolation-induced depression-like behavior in male mice

Li, Wei; Niu, Lei; Liu, Zhenghai; Xu, Xuan; Shi, Mei; Zhang, Yuan; Deng, Yi; He, Jie; Yang, Xu; Wan, Wei Keat; Sun, Qiumin; Zhong, Xiaolin; Cao, Wenzhi

doi:10.1016/j.neulet.2021.136290

Cited by 14 publications

(3 citation statements)

References 42 publications

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“…Firstly, because caspase-1 is the effector organ responsible for cleaving pro-IL-1β, its inhibitors, such as Ac-YVAD-CMK and VX765, can improve the depressive-like behavior of mice [ 247 , 249 ]. Secondly, the application of NLRP3 inhibitors, such as MCC950 and glibenclamide, unexpectedly prevents inflammation-related depressive-like behavior [ 250 - 252 ]. Thirdly, regulating the upstream molecule of NLRP3 inflammasome activation also yields an antidepressant-like effect.…”

Section: Discussionmentioning

confidence: 99%

Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder

Jiang

2024

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Background: Abundant evidence suggests that inflammatory cytokines contribute to the symptoms of major depressive disorder (MDD) by altering neurotransmission, neuroplasticity, and neu-roendocrine processes. Given the unsatisfactory response and remission of monoaminergic antidepres-sants, anti-inflammatory therapy is proposed as a feasible way to augment the antidepressant effect. Recently, there have been emerging studies investigating the efficiency and efficacy of anti-inflammatory agents in the treatment of MDD and depressive symptoms comorbid with somatic diseases. Methods: In this narrative review, prospective clinical trials focusing on anti-inflammatory treatment for depression have been comprehensively searched and screened. Based on the included studies, we summarize the rationale for the anti-inflammatory therapy of depression and discuss the utilities and confusions regarding the anti-inflammatory strategy for MDD. Results: This review included over 45 eligible trials. For ease of discussion, we have grouped them into six categories based on their mechanism of action, and added some other anti-inflammatory modalities, including Chinese herbal medicine and non-drug therapy. Pooled results suggest that anti-inflammatory therapy is effective in improving depressive symptoms, whether used as monotherapy or add-on therapy. However, there remain confusions in the application of anti-inflammatory therapy for MDD. Conclusion: Based on current clinical evidence, anti-inflammatory therapy is a promisingly effective treatment for depression. This study proposes a novel strategy for clinical diagnosis, disease classifica- tion, personalized treatment, and prognostic prediction of depression. Inflammatory biomarkers are recommended to be assessed at the first admission of MDD patients, and anti-inflammatory therapy are recommended to be included in the clinical practice guidelines for diagnosis and treatment. Those patients with high levels of baseline inflammation (e.g., CRP > 3 mg/L) may benefit from adjunctive anti-inflammatory therapy.

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Section: Discussionmentioning

confidence: 99%

Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder

Jiang

2024

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“…The forced swimming test (FST) was performed according to our previous study (Li, Niu, et al, 2021). The mice were placed in a clear plastic cylinder (25 cm high and 15 cm in diameter) filled with water (23 ± 2 C) to a depth of 15 cm.…”

Section: Forced Swimming Testmentioning

confidence: 99%

Betaine prevents cognitive dysfunction by suppressing hippocampal microglial activation in chronic social isolated male mice

Shi

Sun³

et al. 2023

Phytotherapy Research

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Chronic social isolation (SI) stress, which became more prevalent during the COVID‐19 pandemic, contributes to abnormal behavior, including mood changes and cognitive impairment. Known as a functional nutrient, betaine has potent antioxidant and anti‐inflammatory properties in vivo. However, whether betaine can alleviate the abnormal behavior induced by chronic SI in mice remains unknown. In this study, we investigated the efficacy of betaine in the treatment of behavioral changes and its underlying mechanism. Three‐week‐old male mice were randomly housed for 8 weeks in either group housing (GH) or SI. The animals were divided into normal saline‐treated GH, normal saline‐treated SI, and betaine‐treated SI groups in the sixth week. The cognitive and depression‐like behavior was determined in the eighth week. We found that long‐term betaine administration improved cognitive behavior in SI mice but failed to prevent depression‐like behavior. Moreover, long‐term betaine administration inhibited hippocampal microglia over‐activation and polarized microglia toward the M2 phenotype, which effectively inhibited the expression of inflammatory factors in SI mice. Finally, the protective effect of betaine treatment in SI mice might not be due to altered activity of the hypothalamic–pituitary–adrenal axis. Collectively, our findings reveal that betaine can improve SI‐induced cognitive impairment, thus providing an alternative natural source for the prevention of memory loss caused by SI or loneliness.

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“…Clinical investigations indicated that patients with major depression have higher levels of NLRP3 inflammasome − compared with those in the healthy control. Several previous studies also found that inhibiting NLRP3 could alleviate depression-like symptoms in rodents. − Therefore, it is rational to predict that NLRP3 is a promising target for depression treatment. CY-09 is a selective and direct NLRP3-inhibitor which binds to the ATP-binding motif of the NLRP3 NACHT domain and causes the inhibition of NLRP3 inflammasome .…”

Section: Introductionmentioning

confidence: 98%

CY-09 Alleviates the Depression-like Behaviors via Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation in Lipopolysaccharide-Induced Mice

Wang

Liu

Zhang

et al. 2022

ACS Chem. Neurosci.

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Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.

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Inhibition of the NLRP3 inflammasome with MCC950 prevents chronic social isolation-induced depression-like behavior in male mice

Cited by 14 publications

References 42 publications

Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder

Cool the Inflamed Brain: A Novel Anti-inflammatory Strategy for the Treatment of Major Depressive Disorder

Betaine prevents cognitive dysfunction by suppressing hippocampal microglial activation in chronic social isolated male mice

CY-09 Alleviates the Depression-like Behaviors via Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation in Lipopolysaccharide-Induced Mice

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