Abstract WP282: Neurofunctional improvement by MCC950 treatment in aging mice with stroke.

Background: The inflammatory cascade worsens tissue injury and clinical outcomes in acute stroke. The NLRP3 inflammasome plays a central role in the innate immune system. Aged humans and aged mice exhibit chronic sterile inflammation, known as “inflammaging,” with chronic activation of the innate immune system. Our central hypothesis is that the inhibition of the NLRP3 inflammasome will improve long-term functional outcome in aged mice subjected to middle cerebral artery occlusion. Methods: We randomized 30 aging mice to MCC950, a specific inhibitor of NLRP3, 10 mg IP daily (N=15) or placebo (NS IP) (N=15) within 4 hours of stroke then daily for 30 days. We measured the Neurological deficit score, corner test, balance beam walking, novel object recognition, neuro battery test and Y maze at day 30 post stroke Results: Mice treated with MCC950 showed significant improvement in Bederson Neuroscore (p=0.0336; CI: -1.492 to -0.008) t at 48h. In the corner test on Day 30 there were significant changes (p=0.0414; CI: -4.893 to -0.1074) in right preferences, but nonsignificant changes (p=0.215) were observed on day 7. Similarly, we found significant improvement in beam walk (P=0.045; CI: -7.385 to -0.083) and hanging wire (p=0.0015; CI: 22.79 to 79.15) tests in MCC950 treated mice compared to vehicle treated mice treated stroke mice. Interestingly, MCC950 treatment significantly improved the Neuroscore (p=0.047; CI: -1.492 to -0.008) and Neuroscore battery score (p=0.0363; CI: -4.178 to -0.155) at d30. A Y maze test showed a significant number (p=0.0384; CI: 0.2387 to 7.928) of arms entries indicates improved exploration and locomotor activity in MCC950 treated mice. However, in cognitive test NOR test, we could not find significant improvement by MCC950 treatment. Conclusions: Inhibition of the NLRP3 inflammasome with MCC 950 is effective at improving long term functional outcome in aged mice. NLRP3 inhibitors are a promising treatment for acute stroke.