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

Abstract

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.

Development and Evaluation of a Novel Mouse Model of Asphyxial Cardiac Arrest Revealed Severely Impaired Lymphopoiesis After Resuscitation

“…Consistent with previous reports that used other CA/CPR models, 16 , 25 we found strong activation of astrocytes and microglia, especially in the hippocampal region, and a considerable number of monocytes and neutrophils infiltrated from the blood into the brain after CA/CPR. Critically, a characteristic immunosuppression phenotype, as revealed in our recent report using a KCl‐mediated CA model, and which is corroborated by clinical immune manifestations, 16 , 27 , 28 , 29 is also evident in young adult and aged mice after asphyxial CA/CPR. We further discovered that in the thymus, the number of double‐positive T cells became largely depleted, and similarly in the bone marrow, the number of B progenitors was massively decreased.…”

Neuroinflammation in Alzheimer’s Disease

“…Novel specific inhibitors of the NLRP3 inflammasome are currently in pre-clinical or clinical trials [382] (ifmthera.com/pipeline). MCC950 (also known as CP-456,773 and CRID-3), a potent inhibitor of NLRP3, promotes microglial clearance of Aβ, reduces Aβ accumulation, and improves cognitive function in APP/PS1 mice [383][384][385][386]. Both MCC950 and Inzomelid, another potent, selective, brain-penetrant NLRP3 inflammasome inhibitor, are expected to move into Phase II trials for a range of disorders, including Parkinson's, Alzheimer's and, motor neurone disease (https://www.europeanpharmaceuticalreview.com/news/1112 01/patents-for-nlrp3-inflammasome-inhibiting-compounds-granted-in-us-and-europe/.…”

Mitochondria as a Cellular Hub in Infection and Inflammation

“…In a colitis mouse model, it was shown that MitoQ suppressed NLRP3 inflammasome activation [ 237 ]. MCC950 is a molecule that inhibits both the canonical and non-canonical inflammasome pathways, preventing its formation [ 258 , 259 , 260 ]. This molecule was shown to reduce neuroinflammation in study models of Alzheimer’s disease [ 238 , 261 ].…”