Propofol Inhibits NLRP3 Inflammasome and Attenuates Blast-Induced Traumatic Brain Injury in Rats

Ma, Jie; Xiao, Wenjing; Wang, Junrui; Wu, Juan; Ren, Jiandong; Hou, Jing; J, Gu; Fan, Kun; Yu, Bo

doi:10.1007/s10753-016-0446-8

Cited by 67 publications

(69 citation statements)

References 37 publications

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“…Similarly, another paper studying the effect of propofol in rats subjected to blast TBI demonstrated a reduced NLRP3 activation and a consequent ameliorated brain damage due to the antioxidant and ROS scavenger effect of propofol (Ma et al, 2016). This NLRP3 blocking strategy is again rather indirect than direct.…”

Section: Discussionmentioning

confidence: 99%

“…The few papers, so far published on the role of NLRP3 in TBI used indirect strategies to prevent NLRP3 activation (Liu et al, 2013; Dong et al, 2016; Ma et al, 2016; Wei et al, 2016; Lin et al, 2017). A study using telmisartan in mice subjected to cold brain injury showed that the treatment reduced oxidative stress and brain oedema, as a consequence NLRP3 and IL-1b production were decreased; however, the effect on this pathway is rather indirect than direct (Wei et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury

et al. 2017

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Treatment for traumatic brain injury (TBI) remains elusive despite compelling evidence from animal models for a variety of therapeutic targets. The activation of the NLRP3 (Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome has been proposed as key point in the brain damage associated with TBI. NLRP3 was tested as potential target for reducing neuronal loss and promoting functional recovery in a mouse model of TBI. Male NLRP3-/- (n = 20) and wild type (n = 27) mice were used. A closed TBI model was performed and inflammatory and apoptotic markers were evaluated. A group of WT mice also received BAY 11-7082, a NLRP3 inhibitor, to further evaluate the role of this pathway. At 24 h following TBI NLRP3-/- animals demonstrated a preserved cognitive function as compared to WT mice, additionally brain damage was less severe and the inflammatory mediators were reduced in brain lysates. The administration of BAY 11-7082 in WT animals subjected to TBI produced overlapping results. At day 7 histology revealed a more conserved brain structure with reduced damage in TBI NLRP3-/- animals compared to WT. Our data indicate that the NLRP3 pathway might be exploited as molecular target for the short-term sequelae of TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury

et al. 2017

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“…Beyond neurodegenerative diseases, inflammasome forming NLRs have also been found to significantly modulate various pathologic features of both traumatic and non-traumatic brain injury. Of the inflammasome forming NLRs in brain injury, the NLRP1 and NLRP3 inflammasomes are the best characterized in mice and the majority of studies have focused on mechanisms associated with regulating IL-1β/IL-18 and pyroptosis (6–8, 45, 50). However, aside from the inflammasome, there is a paucity of data pertaining to the role of non-inflammasome forming regulatory NLRs in brain injury.…”

Section: Discussionmentioning

confidence: 99%

“…Several inflammasome forming NLRs have been evaluated in the context of brain injury. For example, multiple studies have suggested that NLRP1 and NLRP3 may play critical regulatory roles in TBI in both humans and rodents (6–8). Moreover, NLRC4 and AIM2 have also been implicated in contributing to non-traumatic brain injury in stroke models (9).…”

Section: Introductionmentioning

confidence: 99%

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Theus

Brickler

Meza

et al. 2017

The Journal of Immunology

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Traumatic and non-traumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity and free radical release contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we utilized Nlrx1−/− mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). Here, we show that the Nlrx1−/− mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-κB signaling cascade is significantly up-regulated in the Nlrx1−/− animals. This up-regulation is associated with increased microglia and macrophage populations in the cortical lesion. Utilizing a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-κB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

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“…Protein levels of NLRP3, active caspase-1, and IL-18 all gradually increased over the course of 7 days in cortical tissue ipsilateral to the contusion, while levels of IL-1β rose at 6 h post-injury and declined over the course of 7 days to sham levels [54]. In support of the role of NLRP3 in TBI, another animal study showed that the expression of NLRP3, caspase-1, and thioredoxin-interacting protein (TXNIP), a regulator of NLRP3 activity, were all increased in the cerebral cortex of rats at 12 and 24 h post-blast injury [55]. In a luidpercussion model of TBI in rats, NLRP1 inlammasome complexes containing ASC, caspase-1, caspase-11, XIAP, and pannexin-1 with resultant caspase-1 activation and XIAP cleavage were present in injured cortical lysate at 4 h post-injury.…”

Section: The Inlammasome and Pro-inlammatory Cytokine Releasementioning

confidence: 93%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Propofol Inhibits NLRP3 Inflammasome and Attenuates Blast-Induced Traumatic Brain Injury in Rats

Cited by 67 publications

References 37 publications

Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury

Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

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