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首页> 外文期刊>Journal of neuroinflammation >Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease
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Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease

机译：肿瘤坏死因子-α合成抑制剂3,6'-dithiothalidomide减轻神经炎症和阿尔茨海默氏病动物模型中炎症，阿尔茨海默氏病和行为缺陷的标志物

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Background Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD. Methods The potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide. Results 3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. Conclusions Our data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.
机译：背景技术神经炎症实际上与所有主要的神经退行性疾病有关，包括阿尔茨海默氏病（AD）。尽管尚不清楚神经炎症是否是这些疾病背后的驱动力，但有力的证据暗示其在加剧疾病进展中的作用，其关键因素是有效的促炎性细胞因子TNF-α。通常在AD的临床和动物模型中检测到TNF-α水平升高。方法在神经炎症的细胞模型和啮齿动物模型中研究了新型的TNF-α降低剂3,6'-dithiothalidomide的潜在益处，特别是AD。其中包括由脂多糖（LPS）和Aβ1-42激发引起的中枢和全身炎症，以及慢性3,6'-二硫代thaliodmide对3xTg-AD小鼠的生化和行为评估。结果3,6'-Dithiothaliodmide降低了LPS激活的巨噬细胞样细胞（RAW 264.7细胞）中的TNF-α，亚硝酸盐（氧化损伤的指标）并分泌了淀粉样前体蛋白（sAPP）。这转化为急性LPS攻击的大鼠中枢和全身TNF-α的减少，以及在LPS慢性中枢攻击后神经炎性标志物的减少和神经元可塑性的恢复。在以Aβ1-42肽集中攻击的小鼠中，先前的全身3,6'-二硫代沙利度胺可抑制Aβ诱导的记忆功能障碍，小胶质细胞活化和神经元变性。长期向3xTg-AD小鼠的老年症状队列给药3,6'-dithiothalidomide可降低AD的多种标志性特征，包括磷酸化的tau蛋白，APP，Aβ肽和Aβ斑块数，以及记忆功能的缺陷，降低至年轻儿童的水平成年认知能力未受损的3xTg-AD小鼠。发现在较老的有症状药物治疗的3xTg-AD小鼠中，与媒介物治疗的小鼠相比，突触蛋白，SNAP25和突触素的水平升高，这表明在药物治疗过程中突触功能得以保持。结论我们的数据表明3,6'-二硫代沙利度胺在神经炎症和AD的环境中具有强大的有益作用，支持神经炎症和TNF-α在疾病进展和靶向治疗中的作用，作为临床治疗的手段。

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