Department of Orthopedics, The First People's Hospital of Xianyan, Xianyan, 710043, China.
Department of Orthopedics, No.215 Hospital of Shanxi Nuclear Industry, Xianyan, 710043, China.
Biochem Biophys Res Commun. 2019 Aug 27;516(3):991-998. doi: 10.1016/j.bbrc.2019.06.118. Epub 2019 Jul 2.
Spinal cord injury (SCI) is terrible damage leading to the deficiencies and results in infinite inconvenience to sufferers. The effective treatment for SCI still meets a larger number of problems. Herein, the underlying molecular mechanism and novel therapy of SCI are urgently to investigate. Arachidonate 12-lipoxygenase (ALOX12) is widely expressed in various cell types and plays important role in modulating different cellular processes, such as platelet aggregation, cell migration and cancer cell proliferation. Nevertheless, the effects of ALOX12 on SCI are unclear. In the study, SCI model was established in wild type (WT) mice and ALOX12 knockout mice. First, ALOX12 expression was up-regulated in spinal cord tissues of WT mice after SCI. ALOX12-knockout mice exhibited improved behavior after SCI operation. Glial activation triggered by SCI was also alleviated in mice with the loss of ALOX12, as evidenced by the down-regulated expression of glial fibrillary acidic protein (GFAP) and Iba-1 in spinal cord samples. Further, SCI-induced inflammation was markedly prevented in ALOX12-knockout mice through blocking inhibitor of NF-κB α (IκBα)/nuclear factor-κB (NF-κB) pathway signaling. Additionally, reducing ALOX12 expression attenuated apoptosis in spinal cord tissues of SCI mice by decreasing Cyto-c, cleaved Caspase-3 and poly (ADP-ribose) polymerases (PARP) expression. The protective role of ALOX12-decrease against SCI was verified in LPS-incubated glial cells through repressing inflammatory response and apoptotic formation. Moreover, transgenic mice with ALOX12 over-expression showed accelerated SCI, associated with intensified inflammation and apoptosis. Based on these results, strategies for inhibiting ALOX12 could be used to prevent SCI development by repressing inflammation and apoptosis.
脊髓损伤（SCI）是一种可怕的损伤，导致功能缺陷，并给患者带来无尽的不便。有效的 SCI 治疗方法仍存在许多问题。因此，迫切需要研究 SCI 的潜在分子机制和新疗法。花生四烯酸 12-脂氧合酶（ALOX12）广泛表达于各种细胞类型，在调节血小板聚集、细胞迁移和癌细胞增殖等不同细胞过程中发挥重要作用。然而，ALOX12 对 SCI 的影响尚不清楚。在这项研究中，在野生型（WT）小鼠和 ALOX12 基因敲除（KO）小鼠中建立了 SCI 模型。首先，SCI 后 WT 小鼠脊髓组织中 ALOX12 表达上调。ALOX12 基因敲除小鼠 SCI 手术后行为改善。SCI 引起的小胶质细胞激活也在 ALOX12 缺失的小鼠中得到缓解，脊髓样本中胶质纤维酸性蛋白（GFAP）和 Iba-1 的表达下调证实了这一点。进一步研究发现，通过阻断核因子-κB（NF-κB）信号通路中的抑制物 IκBα，ALOX12 基因敲除小鼠的 SCI 诱导性炎症明显受到抑制。此外，通过降低 Cyto-c、cleaved Caspase-3 和多聚（ADP-核糖）聚合酶（PARP）的表达，减少 ALOX12 表达可减轻 SCI 小鼠脊髓组织中的细胞凋亡。通过抑制炎症反应和细胞凋亡，在脂多糖孵育的神经胶质细胞中证实了 ALOX12 减少对 SCI 的保护作用。此外，过表达 ALOX12 的转基因小鼠 SCI 加重，伴有炎症和细胞凋亡加剧。基于这些结果，抑制 ALOX12 的策略可用于通过抑制炎症和细胞凋亡来预防 SCI 的发生。
