Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage.

Abstract

BACKGROUND AND PURPOSE:

Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain-containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice.

METHODS:

In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection.

RESULTS:

MCC950 reduced IL-1β (interleukin-1β) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1+ myeloid cells.

CONCLUSIONS:

These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.

• Authors: Honglei Ren, Ying Kong, Zhijia Liu, Dongyun Zang, Xiaoxia Yang, Kristofer Wood, Minshu Li, Qiang Liu
• Journal: Stroke (Stroke) Vol. 49 Issue 1 Pg. 184-192 (01 2018) ISSN: 1524-4628 [Electronic] United States
• PMID: 29212744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors.

Chemical References

• IL1B protein, mouse
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse

Topics

• Animals
• Brain Injuries (drug therapy, etiology, metabolism, pathology)
• Cerebral Hemorrhage (complications, drug therapy, metabolism, pathology)
• Female
• Interleukin-1beta (metabolism)
• Male
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, metabolism)