A Novel-designed sulfonylurea compound for Vascular Dementia Therapy

总结

Summary Inflammation plays important roles in the progression of vascular dementia, and targeting inflammation will give a great promise for slowing the progression of vascular dementia and improving cognitive functions. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in regulation of endothelial cell and microglia-induced inflammation. Elevated NLRP3 expression in microglia has been implicated in pathogenesis of vascular dementia. Inhibition of microglia-and brain endothelial cell-mediated inflammation by targeting aberrant NLRP3 activation has emerged as a novel, promising therapeutic approach for treatment of vascular dementia and other neurodegenerative disorders. Our preliminary data show that AMS-17, a novel molecule modified from sulfonylurea compound, has anti-inflammatory effect against LPS-induced inflammation in microglia by inhibiting activities of the NLRP3. Furthermore, AMS-17 improves cognitive functions and protects neurons from death in mouse vascular dementia model. This proposal is proposed to investigate therapeutic effects and elucidate its mechanism of action using vascular dementia model in mouse. Our goal is to develop a lead molecule for NLRP3 inhibition with high selectivity, adequate metabolic stability, and low toxicity that can be used to improve cognitive outcomes of vascular dementia. If success, the lead molecule will give a new effective treatment approach for vascular dementia and other neurodegenerative diseases. The overall impact of the project is highly significant in advancing drug discovery for brain disease therapy.