The Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China; The Department of Orthopedics, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan, China.
The Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China.
Biomed Pharmacother. 2018 Jan;97:905-910. doi: 10.1016/j.biopha.2017.10.092. Epub 2017 Nov 7.
Spinal cord injury (SCI) is a devastating physical trauma worldwide. The mechanisms of SCI are still not clear and the effective treatment is limited. Lipoxin A4 (LXA4) possesses anti-inflammatory and neuroprotective effects. The present study was designed to further evaluate the molecular mechanisms of LXA4-induced protective effects in a rat model of SCI. We found that LXA4 increased Basso, Beattie and Bresnahan (BBB) scores, increased mechanical paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) to a radiant heat, reduced the lesion volume, decreased Bax mRNA expression and increased Bcl-2 expression after SCI. The phosphorylation of Akt and protein expression of Nrf2 and HO-1 were reduced after SCI. LXA4 treatment significantly inhibited the reduction of Akt phosphorylation and Nrf2 and HO-1 protein expression. Injection of LY294002 notably inhibited the phosphorylation of Akt, and the expression of total Akt and Nrf2 and HO-1 after SCI in LXA4-treated rats. LY294002 prohibited LXA4-induced effects after SCI. shNrf2 injection markedly decreased both Nrf2 and HO-1 expression in LXA4-treated rats after SCI. ZnPP notably decreased HO-1 expression but did not markedly affect Nrf2 expression. shNrf2 and ZnPP prohibited LXA4-induced increase of BBB scores, and PWT and PWL, decrease of lesion volume of spinal cord, reduction of Bax expression and increase of Bcl-2 expression. The results indicate that LXA4 protects against SCI through Akt/Nrf2/HO-1 signaling. The data provide novel insights into the mechanisms of LXA4-mediated neuprotective effects against SCI and suggest that LXA4 may be a potential therapeutic agent for SCI and its associated complications.
脊髓损伤（SCI）是一种全球性的破坏性身体创伤。SCI 的机制尚不清楚，有效的治疗方法有限。脂氧素 A4（LXA4）具有抗炎和神经保护作用。本研究旨在进一步评估 LXA4 在 SCI 大鼠模型中诱导保护作用的分子机制。我们发现，LXA4 增加了 Basso、Beattie 和 Bresnahan（BBB）评分，增加了机械性足底撤回阈值（PWT）和足底撤回潜伏期（PWL）对辐射热的反应，减少了损伤体积，降低了 Bax mRNA 表达，增加了 SCI 后的 Bcl-2 表达。SCI 后 Akt 的磷酸化和 Nrf2 和 HO-1 的蛋白表达减少。LXA4 处理显著抑制了 Akt 磷酸化和 Nrf2 和 HO-1 蛋白表达的减少。LY294002 注射显著抑制了 Akt 的磷酸化，以及 LXA4 处理大鼠 SCI 后总 Akt 和 Nrf2 和 HO-1 的表达。LY294002 阻止了 SCI 后 LXA4 诱导的作用。shNrf2 注射显著降低了 SCI 后 LXA4 处理大鼠中 Nrf2 和 HO-1 的表达。ZnPP 显著降低了 HO-1 的表达，但对 Nrf2 的表达没有显著影响。shNrf2 和 ZnPP 阻止了 LXA4 诱导的 BBB 评分升高、PWT 和 PWL 升高、脊髓损伤体积减小、Bax 表达降低和 Bcl-2 表达升高。结果表明，LXA4 通过 Akt/Nrf2/HO-1 信号通路保护 SCI。这些数据为 LXA4 介导的对 SCI 的神经保护作用的机制提供了新的见解，并表明 LXA4 可能是 SCI 及其相关并发症的一种潜在治疗药物。
