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MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation.

Publication ,  Journal Article
Jiang, M; Li, R; Lyu, J; Li, X; Wang, W; Wang, Z; Sheng, H; Zhang, W; Karhausen, J; Yang, W
Published in: J Neuroinflammation
August 31, 2020

BACKGROUND: Cardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined. METHODS: Mice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated. RESULTS: Using our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced. CONCLUSIONS: Our data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.

Duke Scholars

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Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

August 31, 2020

Volume

17

Issue

1

Start / End Page

256

Location

England

Related Subject Headings

  • Survival Rate
  • Sulfonamides
  • Recovery of Function
  • Neurology & Neurosurgery
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Inbred C57BL
  • Mice
  • Interleukin-1beta
  • Inflammasomes
  • Indenes
 

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Jiang, M., Li, R., Lyu, J., Li, X., Wang, W., Wang, Z., … Yang, W. (2020). MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation. J Neuroinflammation, 17(1), 256. https://doi.org/10.1186/s12974-020-01933-y
Jiang, Maorong, Ran Li, Jingjun Lyu, Xuan Li, Wei Wang, Zhuoran Wang, Huaxin Sheng, Weiguo Zhang, Jörn Karhausen, and Wei Yang. “MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation.J Neuroinflammation 17, no. 1 (August 31, 2020): 256. https://doi.org/10.1186/s12974-020-01933-y.
Jiang M, Li R, Lyu J, Li X, Wang W, Wang Z, et al. MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation. J Neuroinflammation. 2020 Aug 31;17(1):256.
Jiang, Maorong, et al. “MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation.J Neuroinflammation, vol. 17, no. 1, Aug. 2020, p. 256. Pubmed, doi:10.1186/s12974-020-01933-y.
Jiang M, Li R, Lyu J, Li X, Wang W, Wang Z, Sheng H, Zhang W, Karhausen J, Yang W. MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation. J Neuroinflammation. 2020 Aug 31;17(1):256.
Journal cover image

Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

August 31, 2020

Volume

17

Issue

1

Start / End Page

256

Location

England

Related Subject Headings

  • Survival Rate
  • Sulfonamides
  • Recovery of Function
  • Neurology & Neurosurgery
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Inbred C57BL
  • Mice
  • Interleukin-1beta
  • Inflammasomes
  • Indenes