A small molecule NLRP3 inhibitor improves cognitive functions in the mouse model of Vascular dementia 2758

Description Inhibition of the NLRP3 inflammasome has emerged as a promising approach for the treatment of vascular dementia (VaD). We previously reported the development of a natural product-inspired small molecule NLRP3 inhibitor, AMS-17. AMS-17 inhibited microglial inflammation and lowered the expression of the NLRP3 inflammasome and its downstream components and cytokines, including, caspase-1, tumor necrosis factor-α, and IL-1β. We examined the neuroprotective role of AMS-17 in vivo using bilateral carotid artery stenosis (BCAS) mouse model of VaD. Mice were divided in Sham, VaD + Vehicle and VaD + AMS-17 (administered inrtaperitoneally at 20 mg/kg for five consecutive days). In Y-maze test and Morris Water Maze assessments, we observed that AMS-17 improved cognition in BCAS mouse model of VaD. Fluoro-Jade C staining revealed that AMS-17 lowered the number of degenerating neurons in the brain cortex. Using fibrinogen deposition as a marker for blood-brain barrier (BBB) leakage, we observed the protective effect of AMS-17 on BBB integrity. Additionally, AMS-17 inhibited microglial activation in VaD mice, suppressed the expressions of the NLRP3 inflammasome and associated proteins in the cortex of VaD mice, and improved myelin repair. AMS-17 lowered the levels of proinflammatory TNF-α, IL-1β, and increased the levels of IL-4. AMS-17 was identified as the inhibitor of the Hippo pathway. Our study provides strong evidence for the therapeutic utility of the AMS-17 for VaD treatment. Funding Sources Supported by NIH/NINDS 7R21NS129478-03 and 1R21NS133895-01.