Institute of Neurological Disease, West China Hospital, Sichuan University & The Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China.
Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China.
CNS Neurosci Ther. 2022 Dec;28(12):2011-2023. doi: 10.1111/cns.13930. Epub 2022 Aug 2.
Fibrotic scars composed of a dense extracellular matrix are the major obstacles for axonal regeneration. Previous studies have reported that antitumor drugs promote neurofunctional recovery.
We investigated the effects of 5-fluorouracil (5-FU), a classical antitumor drug with a high therapeutic index, on fibrotic scar formation, axonal regeneration, and functional recovery after spinal cord injury (SCI).
5-FU administration after hemisection SCI improved hind limb sensorimotor function of the ipsilateral hind paws. 5-FU application also significantly reduced the fibrotic scar formation labeled with aggrecan and fibronectin-positive components, Iba1 /CD11b macrophages/microglia, vimentin, chondroitin sulfate proteoglycan 4 (NG2/CSPG4), and platelet-derived growth factor receptor beta (PDGFRβ) pericytes. Moreover, 5-FU treatment promoted stromal cells apoptosis and inhibited fibroblast proliferation and migration by abrogating the polarity of these cells and reducing matrix metalloproteinase 9 expression and promoted axonal growth of spinal neurons via the neuron-specific protein doublecortin-like kinase 1 (DCLK1). Therefore, 5-FU administration impedes the formation of fibrotic scars and promotes axonal regeneration to further restore sensorimotor function after SCI.
由致密细胞外基质组成的纤维疤痕是轴突再生的主要障碍。先前的研究报道，抗肿瘤药物可促进神经功能恢复。
我们研究了经典抗肿瘤药物 5-氟尿嘧啶（5-FU）对纤维化疤痕形成、轴突再生和脊髓损伤（SCI）后功能恢复的影响。
SCI 半横切后给予 5-FU 治疗可改善同侧后足的后肢感觉运动功能。5-FU 还显著减少了软骨素蛋白多糖 4（NG2/CSPG4）、血小板衍生生长因子受体β（PDGFRβ）周细胞、聚集蛋白聚糖和纤维连接蛋白阳性成分、Iba1/CD11b 巨噬细胞/小胶质细胞、波形蛋白等纤维疤痕形成的标志物。此外，5-FU 通过破坏细胞极性、降低基质金属蛋白酶 9 表达和促进神经元特异性蛋白双皮质样激酶 1（DCLK1）来抑制成纤维细胞增殖和迁移，促进基质细胞凋亡，从而促进轴突生长。因此，5-FU 可抑制纤维疤痕的形成，促进轴突再生，从而进一步恢复 SCI 后的感觉运动功能。
