Department of Neurosurgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Department of Neurosurgery, Shandong Second Provincial General Hospital, Jinan, Shandong, 250022, China.
Department of Otorhinolaryngology-Head and Neck Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, Shandong 250001, China.
Int Immunopharmacol. 2022 Feb;103:108486. doi: 10.1016/j.intimp.2021.108486. Epub 2021 Dec 29.
Compelling evidence has confirmed that inflammatory pathways involving TLR4-regulated cytokines and immune cells are vitallyimportant for the pathogenesis of posthemorrhagic hydrocephalus (PHH), hinting that pharmacological prevention of PHH is feasible. TAK-242, as a toll-like receptor 4 (TLR4) inhibitor, downregulates TLR4-induced inflammatory responses and becomes a potent and noveltherapeuticdrugcandidatefor PHH. In the present study, we investigate whether TAK-242 protects against hydrocephalus and improves the prognosis of intraventricular hemorrhage (IVH). We also explore the possible role of TAK-242 for the regulation of TLR4-NF-κB signaling pathway. A model of PHH was conducted in 6-week-old Male Sprague-Dawley (SD) rats. The rats were divided into four main groups, including the sham, IVH + vehicle, IVH + TAK-242 and IVH groups. Magnetic resonance imaging (MRI) was applied to measure the lateral ventricle volume. Western blot (WB) and immunofluorescence (IF) were applied to detect the expression of TLR4, NF-κB, fibronectin and laminin. A combined scoring system and Morris water maze were employed to evaluate neurological functions after IVH. We found that IVH induced heightened activation of TLR4-NF-κB signaling pathway. We observed the increased lateral ventricular volume, elevation of NF-κB in choroidplexus, as well as fibronectin and laminin in the subarachnoid space (SAS) and ventricular wall after IVH. Obviously, TAK-242 treatment effectively inhibited the up-regulation of NF-κB, fibronectin, laminin and significantly alleviated ventriculomegaly after IVH. Importantly, TAK-242 improved neurocognitive deficits after PHH. In conclusion, TAK-242 attenuated IVH-induced hydrocephalus and improved the prognosis of PHH. The underlying mechanism involved the TAK-242-mediated downregulation of TLR4-NF-κB signaling pathway.
有充分证据证实，涉及 TLR4 调控细胞因子和免疫细胞的炎症通路对于出血后脑积水（PHH）的发病机制至关重要，这提示 PHH 的药物防治具有可行性。TAK-242 作为 Toll 样受体 4（TLR4）抑制剂，可下调 TLR4 诱导的炎症反应，成为 PHH 的一种有潜力的新型治疗药物候选物。本研究旨在探讨 TAK-242 是否对脑积水具有保护作用，并改善脑室内出血（IVH）的预后。我们还探讨了 TAK-242 对 TLR4-NF-κB 信号通路调节的可能作用。建立了 6 周龄雄性 Sprague-Dawley（SD）大鼠 PHH 模型。将大鼠分为假手术组、IVH+载体组、IVH+TAK-242 组和 IVH 组。采用磁共振成像（MRI）测量侧脑室容积。采用 Western blot（WB）和免疫荧光（IF）检测 TLR4、NF-κB、纤维连接蛋白和层粘连蛋白的表达。采用联合评分系统和 Morris 水迷宫评估 IVH 后的神经功能。结果发现，IVH 可引起 TLR4-NF-κB 信号通路的高度激活。IVH 后，脉络丛 NF-κB 增加，蛛网膜下腔（SAS）和室壁纤维连接蛋白和层粘连蛋白增加，侧脑室容积增大。TAK-242 治疗可有效抑制 NF-κB、纤维连接蛋白、层粘连蛋白的上调，并显著减轻 IVH 后的脑室扩大。重要的是，TAK-242 改善了 PHH 后的神经认知缺陷。综上所述，TAK-242 减轻了 IVH 引起的脑积水，并改善了 PHH 的预后。其潜在机制涉及 TAK-242 介导的 TLR4-NF-κB 信号通路下调。
