Department of Pathology, Nanjing Medical University, Longmian Avenue 101, Nanjing, 211166, China.
The Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, 211166, China.
J Neuroinflammation. 2020 Feb 17;17(1):61. doi: 10.1186/s12974-020-01744-1.
Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation.
The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis.
Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase.
Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.
阿尔茨海默病（AD）是一个主要的临床问题，但目前针对这种疾病的有效治疗药物明显缺乏。我们研究了姜科植物大高良姜的一种倍半萜烯——莪术酮，在转 APP/PS1 基因小鼠（一种表现出脑淀粉样变性和神经炎症的 AD 啮齿动物模型）中的潜在治疗效果。
培养 N9 小胶质细胞系和原代小胶质细胞，以研究莪术酮对小胶质细胞的影响。用莪术酮处理 APP/PS1 小鼠，评估并比较治疗组和对照组之间的非认知和认知行为损伤。然后处死动物，收集组织进行进一步分析。还通过 RT-PCR、western blot、一氧化氮检测、酶联免疫吸附测定、免疫组织化学、免疫荧光和流式细胞术分析研究了莪术酮的潜在治疗机制和涉及的信号通路。
莪术酮通过抑制丝裂原活化蛋白激酶（MAPK）/核因子-κB 信号通路，在体外抑制促炎细胞因子的表达，并诱导小胶质细胞从经典炎症表型向替代抗炎表型转变。经过 20 天的治疗期，莪术酮显著改善了转 APP/PS1 基因小鼠的非认知和认知行为缺陷。莪术酮显著减少了皮质和海马中的β-淀粉样蛋白沉积，并减轻了促炎小胶质细胞的激活。有趣的是，莪术酮显著增加了所有激活小胶质细胞中抗炎小胶质细胞的比例，这可能通过增强吞噬作用来减少β-淀粉样蛋白沉积。同时，莪术酮还降低了 MAPK 通路的关键分子（如 p38 和细胞外信号调节激酶）的表达。
总体而言，莪术酮有效改善了行为损伤，减轻了神经炎症，减少了转 APP/PS1 基因小鼠的β-淀粉样蛋白沉积。莪术酮在小胶质细胞中表现出显著的抗炎活性，并通过抑制 MAPK 信号通路诱导小胶质细胞从促炎表型向抗炎表型转变，这可能在其神经保护作用中发挥重要作用。我们的结果表明，莪术酮可能是治疗人类神经炎症和神经退行性疾病，特别是 AD 的一种潜在治疗剂。
