NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats

Danielski, Lucinéia Gainski; Giustina, Amanda Della; Bonfante, Sandra; Joaquim, Larissa; Metzker, Kiuanne Lobo; Biehl, Erica; Vieira, Thaynan Cunha; Medeiros, Fabiana Durante de; Rosa, Naiana da; Generoso, Jaqueline S.; Simões, Lutiana R.; Farias, Hémelin Resende; Lemos, Isabela da Silva; Giridharan, Vijayasree V.; Rezin, Gislaine T.; Fortunato, Jucélia Jeremias; Bitencourt, Rafael Mariano de; Streck, Emílio L.; Dal‐Pizzol, Felipe; Barichello, Tatiana; Petronilho, Fabrícia

doi:10.1007/s12035-020-02089-9

Cited by 31 publications

(10 citation statements)

References 63 publications

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“…We observed that MCC950 pretreatment significantly inhibited NLRP3 inflammasome activation and the subsequent IL‐1β and IL‐18 production, without evident impact on TNF‐α levels and ROS production after subarachnoid haemorrhage. Our data were consistent with Danielski et al's work, in which they found MCC950 inhibited NLRP3 infammasome activation and IL‐1β levels in both rat prefrontal cortex and hippocampus but did not reduce TNF‐α levels and oxidative stress in prefrontal cortex (Danielski et al, 2020), while numerous studies have reported that MCC950 could inhibit TNF‐α levels as well as oxidative damage in different diseases models (Perera et al, 2018; Yumnamcha et al, 2019). In fact, we can see that MCC950 had a minor act on TNF and ROS after subarachnoid haemorrhage, although no significant differences were detected.…”

Section: Discussionsupporting

confidence: 93%

“…and IL-18 production, without evident impact on TNF-α levels and prefrontal cortex and hippocampus but did not reduce TNF-α levels and oxidative stress in prefrontal cortex (Danielski et al, 2020), while numerous studies have reported that MCC950 could inhibit TNF-α levels as well as oxidative damage in different diseases models (Perera et al, 2018;Yumnamcha et al, 2019). In fact, we can see that MCC950 had a minor act on TNF and ROS after subarachnoid haemorrhage, although no significant differences were detected.…”

Section: Discussionmentioning

confidence: 57%

“…MCC950, a novel and selective NLRP3 inflammasome inhibitor, was employed in our study (Luo et al, 2019;Ren et al, 2018;Xu et al, 2018). We observed that MCC950 pretreatment significantly inhibited NLRP3 inflammasome activation and the subsequent IL-1β and IL-18 production, without evident impact on TNF-α levels and inhibited NLRP3 infammasome activation and IL-1β levels in both rat prefrontal cortex and hippocampus but did not reduce TNF-α levels and oxidative stress in prefrontal cortex (Danielski et al, 2020), while numerous studies have reported that MCC950 could inhibit TNF-α levels as well as oxidative damage in different diseases models (Perera et al, 2018;Yumnamcha et al, 2019 activation by resveratrol-conditioning induced protection against cerebral ischaemia is effective at early (24 h) and delayed (>7 days) time points after injury (Vellimana et al, 2018). In addition, mice overexpression SIRT1 has preserved cerebral blood flow following bilateral common carotid artery stenosis and bilateral common carotid artery occlusion (Hattori et al, 2014).…”

Section: Discussionmentioning

confidence: 88%

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Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1‐dependent pathway

Zhang

et al. 2021

British J Pharmacology

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Background and Purpose: Dioscin has multiple biological activities and is beneficial for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of dioscin against subarachnoid haemorrhage and the molecular mechanisms involved.Experimental Approach: Dioscin was administered after subarachnoid haemorrhage induced in rats. MCC950, a potent selective nod-like receptor pyrin domaincontaining 3 (NLRP3) inhibitor, was used to suppress NLRP3 and EX527 (selisistat) was used to inhibit sirtuin 1 (SIRT1).

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 88%

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Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1‐dependent pathway

Zhang

et al. 2021

British J Pharmacology

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“…Even if experimental systemic LPS challenge may not completely mimick polymicrobial sepsisthese observations likely reflect important mechanistic aspects of CNS neuroinflammation since this proinflammatory profile has also been identified in other infectious rodent models, e.g. in the cecal ligation and puncture (CLP) model 56 .…”

Section: Discussionmentioning

confidence: 99%

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

Grünewald

Wickel

Hahn

et al. 2021

Preprint

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Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. The underlying pathophysiology of SAE is largely unresolved, thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery of long-term cognitive dysfunction. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.

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“…In LPS-exposed mice, the lack of NADPH oxidase (NOX) reduces the activation of microglia and confers a protective effect against synaptic dysregulation and cognitive impairment following systemic inflammation [ 174 ]. In addition, it has been confirmed that cytosolic receptors of inflammasome proteins are involved in perpetuating neuroinflammation [ 175 ]. The activity of microglia attacked by LPS decreases after NLRP3 inhibition, thereby improving cognitive function in mice [ 176 ].…”

Section: Prospective Interventions Targeting Microglia and Neuroinfla...mentioning

confidence: 99%

The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation

et al. 2022

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Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.

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NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats

Cited by 31 publications

References 63 publications

Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1‐dependent pathway

Cerebroprotection by dioscin after experimental subarachnoid haemorrhage via inhibiting NLRP3 inflammasome through SIRT1‐dependent pathway

Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation

The Key Drivers of Brain Injury by Systemic Inflammatory Responses after Sepsis: Microglia and Neuroinflammation

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