Craft Jeffrey M, Watterson D Martin, Frautschy Sally A, Van Eldik Linda J
Drug Discovery Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Neurobiol Aging. 2004 Nov-Dec;25(10):1283-92. doi: 10.1016/j.neurobiolaging.2004.01.006.
The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (Abeta)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human Abeta1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress Abeta-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.
慢性炎症在疾病进展中的关键作用在多个疾病领域越来越受到重视，尤其是在神经退行性疾病如阿尔茨海默病中。我们报告称，一种最近发现的抑制神经胶质细胞激活的氨基哒嗪（开发用于抑制氧化和炎性细胞因子途径）的晚期干预，可减轻小鼠模型中人类淀粉样β蛋白（Aβ）诱导的神经胶质细胞激活。在脑室内注入人类Aβ1-42开始3周后，外周给予氨基哒嗪MW01-070C，可减少海马体中活化星形胶质细胞和小胶质细胞的数量以及促炎细胞因子白细胞介素-1β、肿瘤坏死因子-α和S100B的水平。神经炎症的抑制与神经元损失减少、海马体中突触功能障碍生物标志物恢复到对照水平以及淀粉样斑块沉积减少相关。这种体内化学生物学方法的结果提供了一个概念验证，即靶向关键的神经胶质细胞炎性细胞因子途径可以在体内抑制Aβ诱导的神经炎症，并由此减轻神经元损伤。
