Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders

Zhou, Keren; Shi, Ligen; Wang, Yan; Chen, Sheng; Zhang, Jianmin

doi:10.1155/2016/9238290

Cited by 151 publications

(141 citation statements)

References 121 publications

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“…In addition to its hypoglycemic effects, glibenclamide has been shown to play a protective role in inflammation‐related disorders, particularly in CNS injury, including traumatic brain injury (Patel, Gerzanich, Geng, & Simard, ; Xu et al, ), ischemia‐reperfusion injury (Abdallah, Nassar, & Abd‐El‐Salam, ; Caffes et al, ; Gao et al, ; Yang et al, ), subarachnoid hemorrhage (SAH) (Simard et al, ; Tosun et al, ), and ICH (Jiang et al, ; Ma et al, ). Glibenclamide significantly attenuates neuroinflammation, decreases disruption of the BBB, and improves memory function by blocking the Sur1–Trpm4 channel in both experimental SAH and ICH (Zhou, Shi, Wang, Chen, & Zhang, ). Another study suggested that inhibiting microglial Sur1‐Trpm4 channels downregulates the transcription of inducible nitric oxide synthase, leading to reduced activation of microglia and an inflammatory response in the CNS (Kurland et al, ; Tosun et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Glibenclamide ameliorates the disrupted blood–brain barrier in experimental intracerebral hemorrhage by inhibiting the activation of NLRP3 inflammasome

Shen

et al. 2019

Brain and Behavior

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Background Glibenclamide is a widely used sulfonylurea drug prescribed to treat type II diabetes mellitus. Previous studies have demonstrated that glibenclamide has neuroprotective effects in central nervous system injury. However, the exact mechanism by which glibenclamide acts on the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unclear. The purpose of this study was to validate the neuroprotective effects of glibenclamide on ICH and to explore the mechanisms underlying these effects. Methods We investigated the effects of glibenclamide on experimental ICH using the autologous blood infusion model. Glibenclamide was administrated either immediately or 2 hr after ICH. Brain edema was quantified using the wet–dry method 3 days after injury. BBB integrity was evaluated by Evans Blue extravasation and degradation of the tight junction protein zona occludens‐1 (ZO‐1). mRNA levels of inflammatory cytokines were determined by quantitative polymerase chain reaction. Activation of the nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) inflammasome and cell viability were also measured in cerebral microvascular endothelial b.End3 cells exposed to hemin. Neurological changes were evaluated by the Garcia score and rotarod test. Results After ICH, the brain water content, Evans Blue extravasation, and inflammatory cytokines decreased significantly in the ipsilateral hemisphere of the experimental compared to the vehicle group. Glibenclamide treatment and NLRP3 knockdown significantly reduced hemin‐induced activation of the NLRP3 inflammasome, release of extracellular lactate dehydrogenase, apoptosis, and loss of ZO‐1 in b.End3 cells. However, NLRP3 knockdown abolished the protective effect of glibenclamide. Conclusion Glibenclamide maintained BBB integrity in experimental ICH by inhibiting the activation of the NLRP3 inflammasome in microvessel endothelial cells. Our findings will contribute to elucidating the pharmacological mechanism of action of glibenclamide and to developing a novel therapy for clinical ICH.

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Section: Discussionmentioning

confidence: 99%

“…The sterile inflammatory reaction is important in the pathophysiology of ICH (Zhou et al, ). Thrombin and hemoglobin breakdown products after ICH can trigger a sterile inflammatory response through the NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

Glibenclamide ameliorates the disrupted blood–brain barrier in experimental intracerebral hemorrhage by inhibiting the activation of NLRP3 inflammasome

Shen

et al. 2019

Brain and Behavior

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“…However, the NLRP3 inflammasome activation pathway has not yet been fully characterised. The role that calcium signalling, mitochondrial dysfunction, and destabilised lysosomes play in NLRP3 activation has not been fully elucidated (Zhou, Shi, Wang, Chen, & Zhang, 2016). There is a consensus that the canonical activation of the NLRP3 inflammasome requires two signals called "priming" (Signal 1) and "activation" (Signal 2) (Prochnicki, Mangan, & Latz, 2016).…”

Section: Nlrp3 Inflammasome Activation Pathwaymentioning

confidence: 99%

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

Nizami

Hall-Roberts

Warrier

et al. 2019

British J Pharmacology

104

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One of the largest unmet medical needs is a disease‐modifying treatment for Alzheimer's disease (AD). Recently, the role of microglia in disease, particularly AD, has gained great interest, following the identification of several disease risk‐associated genes that are highly expressed in microglia. Microglia play a critical homeostatic role in the brain, with neuroinflammatory and phagocytic mechanisms being of particular importance. Here, we review the role of NLRP3, the complement system, and the triggering receptor expressed in myeloid cells 2 (TREM2) in modulating microglial functions. We have reviewed the targets, their molecular pathways and the therapeutic interventions aimed at modulating these targets, in the hope of discovering a novel therapeutic approach for the treatment of AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…Moreover, IL-18 levels in young animals were slightly higher compared with aged. RT-PCR, reverse-transcription polymerase chain reaction NLRP3 components are induced during the first, priming signal through the toll-like receptor (TLR)-NF-κB pathway (Chang et al, 2015;Zhou, Shi, Wang, Chen, & Zhang, 2016). The subsequent assembly of NLRP3 inflammasome complex occurs during a second signal that can be triggered by several stimuli, both exogenous (including infection, tissue damage, and metabolic dysregulation) and endogenous (including the production of ROS, mitochondrial dysfunction, and accumulation of molecules such as extracellular ATP, hyaluronan, Aβ fibrils, and uric acid crystals; Chang et al, 2015;Walsh et al, 2014;Zhou et al, 2016).…”

Section: Real-time Rt-pcr Analysismentioning

confidence: 99%

Autophagy and NLRP3 inflammasome crosstalk in neuroinflammation in aged bovine brains

Biase

Piegari

Prisco

et al. 2020

Journal Cellular Physiology

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NLRP3 inflammasome is a multiprotein complex that can sense several stimuli such as autophagy dysregulation and increased reactive oxygen species production stimulating inflammation by priming the maturation of proinflammatory cytokines interleukin‐1β and interleukin‐18 in their active form. In the aging brain, these cytokines can mediate the innate immunity response priming microglial activation. Here, we describe the results of immunohistochemical and molecular analysis carried out on bovine brains. Our results support the hypothesis that the age‐related impairment in cellular housekeeping mechanisms and the increased oxidative stress can trigger the inflammatory danger sensor NLRP3. Moreover, according to the recent scientific literature, we demonstrate the presence of an age‐related proinflammatory environment in aged brains consisting in an upregulation of interleukin‐1β, an increased microglial activation and increased NLRP3 expression. Finally, we suggest that bovine may potentially be a pivotal animal model for brain aging studies.

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Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders

Cited by 151 publications

References 121 publications

Glibenclamide ameliorates the disrupted blood–brain barrier in experimental intracerebral hemorrhage by inhibiting the activation of NLRP3 inflammasome

Glibenclamide ameliorates the disrupted blood–brain barrier in experimental intracerebral hemorrhage by inhibiting the activation of NLRP3 inflammasome

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

Autophagy and NLRP3 inflammasome crosstalk in neuroinflammation in aged bovine brains

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