A Novel-designed sulfonylurea compound for Vascular Dementia Therapy

总结 炎症在血管性痴呆的进展中起重要作用， 炎症将为减缓血管性痴呆的进展提供巨大的希望， 改善认知功能。核苷酸结合寡聚化结构域（NOD）样受体 蛋白3（NLRP 3）炎性体在调节内皮细胞中起关键作用， 小胶质细胞诱导的炎症。小胶质细胞中NLRP 3表达的升高与 血管性痴呆的发病机制。抑制小胶质细胞和脑内皮细胞介导的 通过靶向异常NLRP 3激活来治疗炎症已经成为一种新的、有前途的 用于治疗血管性痴呆和其它神经变性疾病的治疗方法。 我们的初步数据表明，AMS-17，一个新的分子修饰的磺酰脲类化合物， 通过抑制活性对LPS诱导的小胶质细胞炎症具有抗炎作用 在NLRP 3。此外，AMS-17改善认知功能，保护神经元免受 小鼠血管性痴呆模型死亡。 这一建议是为了研究治疗效果和阐明其作用机制 采用小鼠血管性痴呆模型。我们的目标是开发NLRP 3的先导分子 具有高选择性、足够的代谢稳定性和低毒性的抑制，其可用于 改善血管性痴呆认知结果。如果成功的话，铅分子会产生一种新的 血管性痴呆和其他神经退行性疾病的有效治疗方法。的 该项目的总体影响在推进脑部疾病药物发现方面非常重要 疗法

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.