Wan Ying, Han Li, Rong Lu, Yang Shuyuan, Song Lu, Wu Na, Liu Zhenguo, Gan Jing
Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gerontology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Neurosci. 2022 Jun 21;16:896322. doi: 10.3389/fnins.2022.896322. eCollection 2022.
Neuroinflammation is involved in the mechanisms of levodopa-induced dyskinesia (LID). The canonical NF-κB activation signaling pathway plays a critical role in the neuroinflammation development and BET protein-induced NF-κB-mediated neuroinflammation. The inhibition of the BET protein function has been reported to alleviate LID; however, its association with the canonical NF-κB signaling pathway in the 6-OHDA-lesioned striatum of the LID rat model remains unknown. Accordingly, we identified the status of the canonical NF-κB signaling pathway in the 6-OHDA-lesioned striatum of the LID rat model and whether the anti-dyskinetic effect of the BET inhibitor JQ1 was associated with its suppression on NF-κB-mediated neuroinflammation.
6-OHDA PD rat models were treated with either L-dopa plus JQ1 or L-dopa alone. L-dopa treatment was given for 2 weeks, and the JQ1 treatment was given for 3 weeks and was initiated a week prior to L-dopa treatment. As a control, the sham rats were treated with JQ1 or Veh for 3 weeks. The ALO AIM assessment and cylinder test were performed during the treatment. Glial activation markers, pro-inflammatory substances, and critical proteins in the canonical NF-κB signaling pathway were tested in the lesioned striatum after the final treatment.
JQ1 effectively alleviated LID without influencing motor improvement. In the lesioned striatum, L-dopa triggered an overactivation of the canonical NF-κB signaling pathway, with an increase in the phospho-IKKα/β, phospho-IκBα, and NF-κB nuclear translocation and its phosphorylation at Ser 536 and Ser 276 sites ( < 0.01 vs. sham group). L-dopa induced an overexpression of the pro-inflammatory substances of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase (iNOS), and the glial activation markers CD68 and GFAP. All the molecular changes were greatly inhibited by JQ1.
L-dopa triggered an overactivation of the canonical NF-κB signaling pathway, leading to an enhanced neuroinflammation response in the 6-OHDA-lesioned striatum of LID rat models. The inhibition of the BET protein function significantly suppressed the activation of the canonical NF-κB signaling pathway in the striatum, alleviating the neuroinflammation response and the severity of LID.
神经炎症参与左旋多巴诱导的异动症（LID）的发病机制。经典的核因子κB（NF-κB）激活信号通路在神经炎症发展以及溴结构域和额外末端结构域（BET）蛋白诱导的NF-κB介导的神经炎症中起关键作用。据报道，抑制BET蛋白功能可减轻LID；然而，在LID大鼠模型的6-羟基多巴胺（6-OHDA）损伤纹状体中，其与经典NF-κB信号通路的关系尚不清楚。因此，我们确定了LID大鼠模型的6-OHDA损伤纹状体中经典NF-κB信号通路的状态，以及BET抑制剂JQ1的抗异动症作用是否与其对NF-κB介导的神经炎症的抑制作用有关。
6-OHDA帕金森病大鼠模型分别接受左旋多巴加JQ1或单独左旋多巴治疗。左旋多巴治疗2周，JQ1治疗3周，且在左旋多巴治疗前1周开始。作为对照，假手术大鼠接受JQ1或溶剂对照治疗3周。治疗期间进行异常不自主运动（AIM）评估和圆筒试验。末次治疗后，检测损伤纹状体中的胶质细胞激活标志物、促炎物质以及经典NF-κB信号通路中的关键蛋白。
JQ1有效减轻LID，且不影响运动功能改善。在损伤纹状体中，左旋多巴引发经典NF-κB信号通路过度激活，磷酸化的抑制性κB激酶α/β（phospho-IKKα/β）、磷酸化的IκBα以及NF-κB核转位及其在丝氨酸536和丝氨酸276位点的磷酸化增加（与假手术组相比，P<0.01）。左旋多巴诱导肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6和诱导型一氧化氮合酶（iNOS）等促炎物质以及胶质细胞激活标志物CD68和胶质纤维酸性蛋白（GFAP）的表达上调。所有这些分子变化均被JQ1显著抑制。
左旋多巴引发经典NF-κB信号通路过度激活，导致LID大鼠模型的6-OHDA损伤纹状体中的神经炎症反应增强。抑制BET蛋白功能可显著抑制纹状体中经典NF-κB信号通路的激活，减轻神经炎症反应和LID的严重程度。
