Aminopyridazines attenuate hippocampus-dependent Behavioral deficits induced by human β-amyloid in a murine model of neuroinflammation
Aminopyridazines attenuate hippocampus-dependent Behavioral deficits induced by human β-amyloid in a murine model of neuroinflammation
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DOI：
10.1385/jmn:24:1:115
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Watterson, DM
中科院分区：
文献类型：
--
作者：
Craft, JM;Van Eldik, LJ;Watterson, DM
神经胶质细胞驱动的神经炎症在阿尔茨海默病（AD）的发病和进展中的重要性促使我们启动了针对阿尔茨海默病特征的神经炎症周期的药物发现工作。我们利用我们的合成化学平台，专注于生物可利用的氨基吡啶嗪作为阿尔茨海默病药物发现的新化学型，开发新的，选择性抑制神经胶质细胞关键炎症和氧化途径。我们发现MW01-070C是一种氨基吡啶，其作用机制不同于非甾体抗炎药和p38 MAPK抑制剂，以剂量依赖的方式减轻β -淀粉样蛋白（Abeta）诱导的神经炎症和神经元功能障碍，并防止Abeta诱导的行为障碍。体内数据是通过小鼠模型获得的，该模型使用脑室内输注人abeta1 -42肽，复制了阿尔茨海默病的许多病理特征，包括神经炎症、神经元和突触变性以及淀粉样蛋白沉积。可量化的终点病理是稳健的，可重复的，快速的发病。我们的研究结果证明了用氨基吡啶类药物靶向神经炎症是一种可行的阿尔茨海默病药物发现方法，具有调节疾病进展的潜力，并证明了该小鼠模型用于临床前筛选靶向阿尔茨海默病相关神经炎症和神经元死亡的化合物的实用性。
The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer's disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates beta-amyloid (Abeta)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Abeta-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of humanAbeta1-42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.