通过抑制促炎性小胶质细胞的极化抑制 NF-κB/DRP1 轴为脊髓损伤后的神经保护提供支持

IF 3.3 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Frontiers in bioscience (Landmark edition) Pub Date : 2024-08-23 DOI:10.31083/j.fbl2908307
Chen Song, Kaihui Zhang, Cheng Luo, Xiaoyong Zhao, Baoshan Xu
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引用次数: 0

摘要

背景:脊髓损伤(SCI)被认为是一种中枢神经系统(CNS)疾病。核因子卡巴B(NF-κB)调节中枢神经系统的炎症反应,并与脊髓损伤的发病机制有关。然而,NF-κB 在 SCI 期间导致神经炎症的机制仍不清楚:采用体重下降法建立 SCI 大鼠模型,并将其分为 Sham 组、SCI 组和 SCI+NF-κB 抑制剂组(每组 6 只大鼠)。我们使用苏木精-伊红染色法(H&E)和 Nissl 染色法检测脊髓的组织学变化。巴索-巴蒂-布雷斯纳汉(Basso-Beattie-Bresnahan,BBB)行为评分用于评估功能性运动恢复情况。小鼠BV2小胶质细胞暴露于脂多糖(LPS),在体外模拟SCI诱导的小胶质细胞炎症:结果:使用JSH-23抑制NF-κB可减轻SCI大鼠脊髓的炎症和神经元损伤,从而改善运动恢复(p < 0.05)。抑制 NF-κB 可降低 CD86、白细胞介素-6(IL-6)、IL-1β 和诱导型一氧化氮合成酶(iNOS)的表达水平,并改善 LPS 处理的小胶质细胞和 SCI 大鼠脊髓中 CD206、IL-4 和组织生长因子-β(TGF-β)的表达水平(p < 0.05)。抑制 NF-κB 还能有效抑制线粒体裂变,这一点可从动态相关蛋白 1(DRP1)在 Ser616 处的磷酸化减少得到证明(p < 0.001):我们的研究表明,抑制 NF-κB/DRP1 轴可防止线粒体分裂并抑制促炎性小胶质细胞极化,从而促进 SCI 神经系统的恢复。因此,靶向 NF-κB/DRP1 轴是治疗 SCI 的一种新方法。
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Inhibiting the NF-κB/DRP1 Axis Affords Neuroprotection after Spinal Cord Injury via Inhibiting Polarization of Pro-Inflammatory Microglia.

Background: 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.

Methods: 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 in vitro.

Results: Inhibition of NF-κB using JSH-23 alleviated inflammation and neuronal injury in SCI rats' spinal cords, leading to improved locomotion recovery (p < 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 (p < 0.05). Inhibition of NF-κB also effectively suppressed mitochondrial fission, evidenced by the reduced phosphorylation of dynamin-related protein 1 (DRP1) at Ser616 (p < 0.001).

Conclusion: 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.

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