Neuroprotection of Glibenclamide against Brain Injury after Cardiac Arrest via Modulation of NLRP3 Inflammasome

Yang, Xiuli; Wang, Zhuoran; Jia, Xiaofeng

doi:10.1109/embc.2019.8857285

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…Other studies [24,58] have reported that, in addition to NLRP3 upregulation, stress increases hippocampal cleaved caspase-1 and IL-1β levels; but we did not observe this effect in our stressed controls. However, we did confirm that global ischemia activated the NLRP3 inflammasome pathway [25][26][27]. This observation supports previous studies showing that NLRP3 inflammasome inhibition reduces inflammation and ameliorates ischemic injury.…”

Section: Effects Of Stress Exposure Prior To Ischemia On Nlrp3 Inflamsupporting

confidence: 91%

“…In pigs, Qian et al [27] observed a similar up-regulation in NLRP3, cleaved caspase-1 and IL-1β as early as 30 h after cardiac arrest. Similarly, Yang et al [26] found an increase in NLRP3 and Caspase-1 at 72 h post-ischemia.…”

Section: Effects Of Stress Exposure Prior To Ischemia On Nlrp3 Inflammentioning

confidence: 74%

“…It is noteworthy that this inflammasome is primed by stress [13,24] and activated following ischemic injury [25]. Inhibiting NLRP3 activation reduces the inflammation associated with poor outcomes in rodent models of brain injury associated with cardiac arrest [26,27].…”

Section: Introductionmentioning

confidence: 99%

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Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

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Section: Effects Of Stress Exposure Prior To Ischemia On Nlrp3 Inflamsupporting

confidence: 91%

Section: Effects Of Stress Exposure Prior To Ischemia On Nlrp3 Inflammentioning

confidence: 74%

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Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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“…IRI stimulates IL-1β, IL-18, and NF-κB, activating the NLRP3 inflammasome, caspase-1, and other downstream mediators resulting in cell death and brain damage ( 92 ). Glibenclamide (GBC), a sulfonylurea drug used for diabetes, has been shown to inhibit the NLRP3 inflammasome pathway, suppress microglia and astrocyte activation, and support favorable neurologic outcomes following rodent CA ( 93 ). Furthermore, the immunomodulatory and antioxidative properties of statins have also shown efficacy in ischemic diseases ( 94 ).…”

Section: Overview Of the Various Cardiac Arrest-mediated Pathway Alterationsmentioning

confidence: 99%

Pharmacological Approach for Neuroprotection After Cardiac Arrest—A Narrative Review of Current Therapies and Future Neuroprotective Cocktail

et al. 2021

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Cardiac arrest (CA) results in global ischemia-reperfusion injury damaging tissues in the whole body. The landscape of therapeutic interventions in resuscitation medicine has evolved from focusing solely on achieving return of circulation to now exploring options to mitigate brain injury and preserve brain function after CA. CA pathology includes mitochondrial damage and endoplasmic reticulum stress response, increased generation of reactive oxygen species, neuroinflammation, and neuronal excitotoxic death. Current non-pharmacologic therapies, such as therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation, have shown benefits in protecting against ischemic brain injury and improving neurological outcomes post-CA, yet their application is difficult to institute ubiquitously. The current preclinical pharmacopeia to address CA and the resulting brain injury utilizes drugs that often target singular pathways and have been difficult to translate from the bench to the clinic. Furthermore, the limited combination therapies that have been attempted have shown mixed effects in conferring neuroprotection and improving survival post-CA. The global scale of CA damage and its resultant brain injury necessitates the future of CA interventions to simultaneously target multiple pathways and alleviate the hemodynamic, mitochondrial, metabolic, oxidative, and inflammatory processes in the brain. This narrative review seeks to highlight the current field of post-CA neuroprotective pharmaceutical therapies, both singular and combination, and discuss the use of an extensive multi-drug cocktail therapy as a novel approach to treat CA-mediated dysregulation of multiple pathways, enhancing survival, and neuroprotection.

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“…Retrospective clinical studies, as well as a prospective phase II pilot study, provide promising results in the use of glibenclamide after cerebral ischemia (86). In a model of cardiac arrest induced by asphyxia with concomitant cardiopulmonary resuscitation, glibenclamide was shown to exert anti-neuroinflammatory effects by downregulating the NLRP3 inflammatory pathway (87).…”

Section: Glibenclamidementioning

confidence: 99%

Neuroinflammation in Post-Ischemic Brain

et al. 2021

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Acute neuroinflammation occurring immediately after cerebral ischemia lasts for a few days.Cytokines and chemokines promote the migration of neutrophils and macrophages to the site of inflammation in the brain. Neuroinflammation lasting 2-6 weeks is known as subacute neuroinflammation, while chronic post-ischemic inflammation lasts for months or years.Macrophages, lymphocytes, and plasma cells predominate in chronic neuroinflammation, in contrast to neutrophils that predominate in acute neuroinflammation. In addition to their harmful impact on the ischemic brain, inflammatory mediators may also exert beneficial effects in stroke recovery. The role of secondary inflammatory cells in the pathophysiology of brain ischemia are still less understood. Late post-ischemic neuroinflammation leads to secondary damage of neuronal cells. In this chapter, the role of leukocytes, T cells, T regs, B cells, neutrophils, macrophages, microglia, astrocytes, cytokines, and transcription factors in the post-ischemic brain are discussed. Post-ischemic thrombo-inflammation and the role of platelets, recently considered as a part of the innate immune system, are also addressed. The current pharmacotherapy and future strategies for the treatment of neuroinflammation in post-ischemic brain as well as the limitations of translation between preclinical and clinical studies are presented.

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Neuroprotection of Glibenclamide against Brain Injury after Cardiac Arrest via Modulation of NLRP3 Inflammasome

Cited by 7 publications

References 26 publications

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Pharmacological Approach for Neuroprotection After Cardiac Arrest—A Narrative Review of Current Therapies and Future Neuroprotective Cocktail

Neuroinflammation in Post-Ischemic Brain

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