Krembil Research Institute, University Health Network, Toronto, Canada.
Faculty of Pharmacy, University of Toronto, Ontario M5S 1A1, Canada.
ACS Chem Neurosci. 2020 Dec 16;11(24):4152-4168. doi: 10.1021/acschemneuro.0c00445. Epub 2020 Nov 23.
The accumulation and deposition of β-amyloid (Aβ) is one postulated cause of Alzheimer's disease (AD). In addition to its direct toxicity on neurons, Aβ may induce neuroinflammation through the concomitant activation of microglia. Emerging evidence suggests that microglia-mediated neuroinflammation plays an important role in the pathogenesis of AD. As brain macrophages, microglia engulf misfolded-Aβ by phagocytosis. However, the accumulated toxic Aβ may paradoxically "hyper-activate" microglia into a neurotoxic proinflammatory and less phagocytotic phenotype, contributing to neuronal death. This study reports that the known drug furosemide is a potential probe molecule for reducing AD-neuroinflammation. Our data demonstrate that furosemide inhibits the secretion of proinflammatory TNF-α, IL-6, and nitric oxide; downregulates the mRNA level of and the protein expression of COX-2, iNOS; promotes phagocytic activity; and enhances the expression of anti-inflammatory IL-1RA and arginase. Our mechanism of action studies further demonstrate that furosemide reduces LPS-induced upregulation of endoplasmic reticulum (ER) stress marker genes, including , , , , and . These data support the observation that furosemide is a known drug with the capacity to downregulate the proinflammatory microglial M1 phenotype and upregulate the anti-inflammatory M2 phenotype, a potentially powerful and beneficial pharmacologic effect for inflammatory diseases such as AD.
β-淀粉样蛋白（Aβ）的积累和沉积是阿尔茨海默病（AD）的一个假定原因。除了对神经元的直接毒性外，Aβ 还可以通过小胶质细胞的伴随激活诱导神经炎症。新出现的证据表明，小胶质细胞介导的神经炎症在 AD 的发病机制中起着重要作用。作为大脑中的巨噬细胞，小胶质细胞通过吞噬作用吞噬错误折叠的 Aβ。然而，积累的有毒 Aβ 可能反常地“过度激活”小胶质细胞，使其成为神经毒性的促炎和吞噬作用降低的表型，导致神经元死亡。本研究报告称，已知药物呋塞米是一种潜在的减少 AD 神经炎症的探针分子。我们的数据表明，呋塞米抑制促炎 TNF-α、IL-6 和一氧化氮的分泌；下调 和 COX-2、iNOS 的 mRNA 水平；促进吞噬作用；并增强抗炎性 IL-1RA 和精氨酸酶的表达。我们的作用机制研究进一步表明，呋塞米降低 LPS 诱导的内质网（ER）应激标记基因的上调，包括 、 、 、 和 。这些数据支持这样的观察结果，即呋塞米是一种已知的药物，具有下调促炎小胶质细胞 M1 表型和上调抗炎 M2 表型的能力，这是一种针对 AD 等炎症性疾病的潜在强大和有益的药理作用。
