Lu Pengfei, Han Donghe, Zhu Kunming, Jin Meihua, Mei Xifan, Lu Haixia
Institute of Neurobiology, Xi'an Jiaotong University Health Science Center, Xi'an.
Department of Neurobiology, Key laboratory of Neurodegenerative Disease, Jinzhou Medical University.
Neuroreport. 2019 Sep 4;30(13):867-874. doi: 10.1097/WNR.0000000000001293.
Because posttraumatic inflammation contributes to the progression of neuron degeneration, attenuating inflammation is important for reducing neural degeneration. Sirtuin 1 (SIRT1) has been shown to play a critical role in the chronic diseases, such as neurodegenerative diseases and aging. However, the role that SIRT1 plays in regulating neuroinflammation in spinal cord injuries (SCIs) remains unclear. In this study, we investigate the effect of SIRT1 on the SCI model and on lipopolysaccharide (LPS)-treated primary microglia using a pharmacological intervention (SRT1720, an agonist of SIRT1). Results showed that SIRT1 levels gradually decreased in spinal cord until the fourth week after SCI, while the level of 8-hydroxy-2'-deoxyguanosine increased. SIRT1 was negatively correlated with the expression of β-catenin following SCI. The administration of SRT1720 significantly improved number of neurons and the Basso, Beattie, and Bresnahan score after SCI. The number of ionizing calcium-binding adaptor molecule 1 (Iba1)-positive microglia, levels of β-catenin and NF-kB p65, and proinflammatory cytokines [tumor necrosis factor alpha and interleukin (IL) 12] decreased significantly after SRT1720 treatment, while IL-10 increased after SCI. Furthermore, both SIRT1 and SRT1720 significantly inhibited β-catenin gene and protein expression; β-catenin transcriptional activity also decreased in a dose-dependent manner following SIRT1 treatment of LPS-treated microglia. These findings suggest that SIRT1 may have a neuroprotective effect by suppressing microglial activation via downregulation of the Wnt/β-catenin signal following SCI.
由于创伤后炎症会促进神经元变性的进展，减轻炎症对于减少神经变性很重要。沉默调节蛋白1（SIRT1）已被证明在诸如神经退行性疾病和衰老等慢性疾病中起关键作用。然而，SIRT1在调节脊髓损伤（SCI）中的神经炎症方面所起的作用仍不清楚。在本研究中，我们使用药理学干预（SRT1720，一种SIRT1激动剂）研究了SIRT1对SCI模型和脂多糖（LPS）处理的原代小胶质细胞的影响。结果显示，在SCI后的第四周之前，脊髓中的SIRT1水平逐渐下降，而8-羟基-2'-脱氧鸟苷的水平升高。SCI后，SIRT1与β-连环蛋白的表达呈负相关。给予SRT1720可显著改善SCI后神经元数量以及Basso、Beattie和Bresnahan评分。SRT1720治疗后，离子钙结合衔接分子1（Iba1）阳性小胶质细胞数量、β-连环蛋白和NF-κB p65水平以及促炎细胞因子[肿瘤坏死因子α和白细胞介素（IL）12]显著降低，而SCI后IL-10升高。此外，SIRT1和SRT1720均显著抑制β-连环蛋白基因和蛋白表达；在对LPS处理的小胶质细胞进行SIRT1处理后，β-连环蛋白的转录活性也呈剂量依赖性降低。这些发现表明，SCI后SIRT1可能通过下调Wnt/β-连环蛋白信号来抑制小胶质细胞活化，从而具有神经保护作用。
