Protection of hUC-MSCs against neuronal complement C3a receptor-mediated NLRP3 activation in CUMS-induced mice

Li, Jing; Tian, Shujuan; Hualong, Wang; wang, Yanyong; Du, Chongbo; Fang, Jiyu; Wang, Xiaoxiao; Wang, Yufeng; Gong, Zhe-Xuan; Yan, Bowei; Wang, Mingwei

doi:10.1016/j.neulet.2020.135485

Cited by 13 publications

(14 citation statements)

References 31 publications

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“…In the present study, we confirmed that the active component Gypenoside XVII could inhibit complement C3/C3aR-mediated synaptic pruning in microglia by CUMS. This result is in agreement with previous observations that treatment with a C3aR antagonist inhibited inflammation in CUMS-induced depression [28].…”

Section: Discussionsupporting

confidence: 94%

“…Recently, a growing number of studies have found that complement-related signaling pathways play an important role in neuropsychiatric diseases, including Alzheimer's disease and depression [26,27]. It was found that stress caused an abnormal activation of complement-mediated synaptic pruning in microglia [28], which provided new ideas for the treatment of depression in the aspect of complement intervention. Complement C3 is a key protein of the complement cascade, and its multiple molecular binding sites are the key to its function.…”

Section: Discussionmentioning

confidence: 99%

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Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

et al. 2022

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Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

et al. 2022

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“…3e). The complement receptor C3aR, a signaling receptor expressed by microglia, can be activated by the C3 cleavage fragment C3a and has been reported to have important roles in chronic unpredictable mild stress (CUMS) mice [43][44][45][46]. We found that the mRNA expression of C3aR was significantly increased in the RSP group but declined in the RSP group treated with BoNT/A (Fig.…”

Section: Reserpine Induced Depression-like Behavior In a Mouse Model ...mentioning

confidence: 79%

Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

Yin

et al. 2023

Acta Pharmacol Sin

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Depression is one of the common non-motor symptoms of Parkinson’s disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 μg/mL in the drinking water) for 10 weeks. From the 10th week, BoNT/A (10 U·kg−1·d−1) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1β in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses.

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“…The hUC-MSCs administration furthermore reversed the elevated levels of NLRP3 and pro-inflammatory cytokines such as TNFa and IL-1b, which might be due to blocking the neuronal complement C3a receptor in the mice hippocampus. 191 One of the main innate immune system effector mechanisms, the complement system, increases the ability of antibodies and phagocytic cells and also promotes inflammation. 192 Activation of the complement system mainly focuses on the cleavage of C3a, the central part of this system, which mediates immunomodulatory signals.…”

Section: Mscs and Their Exosomes Alleviate Cns Diseases By Targeting ...mentioning

confidence: 99%

Mesenchymal stem cells (MSCs) and MSC‐derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome

et al. 2023

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is a multimeric protein complex that is engaged in the innate immune system and plays a vital role in inflammatory reactions. Activation of the NLRP3 inflammasome and subsequent release of proinflammatory cytokines can be triggered by microbial infection or cellular injury. The NLRP3 inflammasome has been implicated in the pathogenesis of many disorders affecting the central nervous system (CNS), ranging from stroke, traumatic brain injury, and spinal cord injury to Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and depression. Furthermore, emerging evidence has suggested that mesenchymal stem cells (MSCs) and their exosomes may modulate NLRP3 inflammasome activation in a way that might be promising for the therapeutic management of CNS diseases. In the present review, particular focus is placed on highlighting and discussing recent scientific evidence regarding the regulatory effects of MSC‐based therapies on the NLRP3 inflammasome activation and their potential to counteract proinflammatory responses and pyroptotic cell death in the CNS, thereby achieving neuroprotective impacts and improvement in behavioral impairments.

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Protection of hUC-MSCs against neuronal complement C3a receptor-mediated NLRP3 activation in CUMS-induced mice

Cited by 13 publications

References 31 publications

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation

Mesenchymal stem cells (MSCs) and MSC‐derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome

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