Graduate School, Tianjin Medical University, 300000 Tianjin, China.
Department of Geriatric Orthopedics, The Second Hospital of Tangshan, 063000 Tangshan, Hebei, China.
Front Biosci (Landmark Ed). 2024 Aug 23;29(8):307. doi: 10.31083/j.fbl2908307.
Spinal cord injury (SCI) is considered a central nervous system (CNS) disorder. Nuclear factor kappa B (NF-κB) regulates inflammatory responses in the CNS and is implicated in SCI pathogenesis. The mechanism(s) through which NF-κB contributes to the neuroinflammation observed during SCI however remains unclear.
SCI rat models were created using the weight drop method and separated into Sham, SCI and SCI+NF-κB inhibitor groups (n = 6 rats per-group). We used Hematoxylin-Eosin Staining (H&E) and Nissl staining for detecting histological changes in the spinal cord. Basso-Beattie-Bresnahan (BBB) behavioral scores were utilized for assessing functional locomotion recovery. Mouse BV2 microglia were exposed to lipopolysaccharide (LPS) to mimic SCI-induced microglial inflammation .
Inhibition of NF-κB using JSH-23 alleviated inflammation and neuronal injury in SCI rats' spinal cords, leading to improved locomotion recovery ( < 0.05). NF-κB inhibition reduced expression levels of CD86, interleukin-6 (IL-6), IL-1β, and inducible Nitric Oxide Synthase (iNOS), and improved expression levels of CD206, IL-4, and tissue growth factor-beta (TGF-β) in both LPS-treated microglia and SCI rats' spinal cords ( < 0.05). Inhibition of NF-κB also effectively suppressed mitochondrial fission, evidenced by the reduced phosphorylation of dynamin-related protein 1 (DRP1) at Ser616 ( < 0.001).
We show that inhibition of the NF-κB/DRP1 axis prevents mitochondrial fission and suppresses pro-inflammatory microglia polarization, promoting neurological recovery in SCI. Targeting the NF-κB/DRP1 axis therefore represents a novel approach for SCI.
脊髓损伤（SCI）被认为是一种中枢神经系统（CNS）疾病。核因子 kappa B（NF-κB）调节 CNS 中的炎症反应，并与 SCI 的发病机制有关。然而，NF-κB 促进 SCI 期间观察到的神经炎症的机制尚不清楚。
使用重物坠落法建立 SCI 大鼠模型，并将其分为假手术（Sham）、SCI 和 SCI+NF-κB 抑制剂组（每组 n = 6 只大鼠）。我们使用苏木精-伊红染色（H&E）和尼氏染色检测脊髓的组织学变化。Basso-Beattie-Bresnahan（BBB）行为评分用于评估功能性运动恢复。用脂多糖（LPS）孵育小鼠 BV2 小胶质细胞模拟 SCI 诱导的小胶质细胞炎症。
使用 JSH-23 抑制 NF-κB 减轻了 SCI 大鼠脊髓中的炎症和神经元损伤，导致运动恢复改善（ < 0.05）。NF-κB 抑制降低了 LPS 处理的小胶质细胞和 SCI 大鼠脊髓中 CD86、白细胞介素 6（IL-6）、IL-1β 和诱导型一氧化氮合酶（iNOS）的表达水平，提高了 CD206、IL-4 和组织生长因子-β（TGF-β）的表达水平（ < 0.05）。NF-κB 抑制还通过减少分裂蛋白 1（DRP1）丝氨酸 616 的磷酸化（ < 0.001）有效抑制线粒体裂变。
我们表明，抑制 NF-κB/DRP1 轴可防止线粒体裂变，并抑制促炎小胶质细胞极化，促进 SCI 后的神经恢复。因此，靶向 NF-κB/DRP1 轴代表了一种治疗 SCI 的新方法。
