Impact Factor 4.300

The world's most-cited Neurosciences journals

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00426

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

Yunxia Fan1, Liwu Du2, Qun Fu3, Jingyun Zhang1, Guomin Li1, Zhiqiang Zhou3 and  Jing Wu4*
  • 1Jiangsu University, China
  • 2Second Military Medical University, China
  • 3Nanjing Medical University, China
  • 4Nanjing University, China

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 or 30% oxygen 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.

Keywords: NLRP3, Neuroinflammation, pyroptosis, cognitive impairments, general anesthesia, Aging

Received: 30 Aug 2018; Accepted: 30 Oct 2018.

Edited by:

Hung-Ming Chang, Taipei Medical University, Taiwan

Reviewed by:

Wenchieh Liao, Chung Shan Medical University, Taiwan
Tzer-Bin Lin, Taipei Medical University, Taiwan  

Copyright: © 2018 Fan, Du, Fu, Zhang, Li, Zhou and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jing Wu, Nanjing University, Nanjing, China, boaz.jing@gmail.com