Inhibiting the NLRP3 Inflammasome With MCC950 Ameliorates Isoflurane-Induced Pyroptosis and Cognitive Impairment in Aged Mice.

Yunxia Fan,Liwu Du,Qun Fu,Guomin Li,Jing Wu,Zhiqiang Zhou,Jingyu Zhang

doi:10.3389/fncel.2018.00426

Abstract

Nod-like receptor protein 3 (NLRP3) inflammasome activation has been implicated in the pathogenesis of general anesthesia (GA)-induced neuroinflammation and cognitive impairment in aged rodents. However, the cellular basis for cognitive impairment is still not fully understood, and effective pharmacologic agents targeting the NLRP3 inflammasome during GA are lacking. This study explores the protective effects of the NLRP3 inflammasome inhibitor MCC950 on pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Seventy-two 15-month-old male C57BL/6 mice were randomized to receive 2 h of 1.5% isoflurane plus 30% oxygen (O2) or 30% O2 alone, respectively. MCC950 (10 mg/kg) or vehicle was intraperitoneally administered 30 min before gas inhalation. Brain tissues were harvested for histochemical analysis and biochemical assays. Learning and memory abilities were evaluated by behavioral tests. We found that isoflurane GA caused upregulations of hippocampal NLRP3, cleaved caspase-1, interleukin-1β (IL-1β), and IL-18 and the activation of pyroptosis, which is NLRP3 inflammasome-dependent; this consequently gave rise to neuronal damage and cognitive impairment in aged mice. Interestingly, pretreatment with NLRP3 inflammasome inhibitor MCC950 not only provided a neuroprotective effect against the inflammasome activation but also ameliorated pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Our data demonstrate that pyroptosis is involved in NLRP3 inflammasome-mediated isoflurane-induced cognitive impairment in aged mice and suggest that inhibiting the NLRP3 inflammasome with MCC950 may have clinically therapeutic benefits for elderly patients undertaking GA.

Highlights

Postoperative cognitive dysfunction (POCD) is a common complication associated with significant morbidity and mortality in elderly patients (Berger et al, 2015; Moskowitz et al, 2017)
Our results showed that the protein levels of NOD-like receptor protein 3 (NLRP3) and cleaved caspase-1 (Figure 1) and the number of NLRP3-positive cells (Figure 2) were increased 24 h after 2 h isoflurane exposure
Our results indicate that isoflurane-induced NLRP3 inflammasome activation is successfully inhibited by MCC950 administration

Summary

Introduction

Postoperative cognitive dysfunction (POCD) is a common complication associated with significant morbidity and mortality in elderly patients (Berger et al, 2015; Moskowitz et al, 2017). The NOD-like receptor protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is the best recognized and most widely studied inflammasome. It regulates the cleavage of caspase-1, which controls the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18 (He et al, 2016a; Dempsey et al, 2017; Jiang et al, 2018). These cytokines are crucial in initiating or amplifying the innate immune response and neuroinflammation following GA. The effects of MCC950 on GA-induced neuroinflammation and cognitive impairment are unknown

Methods

Results

Discussion

Conclusion