Albiflorin Attenuates Neuroinflammation and Improves Functional Recovery After Spinal Cord Injury Through Regulating LSD1-Mediated Microglial Activation and Ferroptosis.

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-01 Epub Date: 2024-02-10 DOI:10.1007/s10753-024-01978-8
Longyu Zhang, Jiao Xu, Shi Yin, Qiang Wang, Zhiwei Jia, Tianlin Wen
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Abstract

Spinal cord injury (SCI) is a serious, prolonged, and irreversible injury with few therapeutic options. Albiflorin (AF) possesses powerful pharmacodynamic properties and exerts protective effects against neuroinflammation. However, no research has examined the neuroprotective effect of AF following SCI. Rats were received laminectomy to establish SCI animal model and treated with AF (20 mg/kg and 40 mg/kg). Behavioral experiments were conducted to assess the impacts of AF on motor function after SCI in rats. Hematoxylin-eosin (HE) staining, Nissl staining, and Prussian Blue staining were performed to observe histological changes, neuronal damage, and iron deposition, respectively. Transmission electron microscope was adopted to observe the ultrastructure of spinal cord tissues. Immunofluorescence assay was performed to examine neurons and microglia. ELISA assay was used to examine the production of cytokines. Western blot assay was used to detect the expression level of ferroptosis-related proteins. Microglia BV-2 cells were induced by LPS to mimic the neuroinflammatory condition. Cell viability was assessed by CCK-8 assay, and lipid peroxidase level was measured by C11 BODIPY 581/591 staining. Molecular docking technology was utilized to confirm the relationship between AF and LSD1. AF improved the motor functional recovery after SCI in rats. Meanwhile, AF attenuated neuron apoptosis and microglia activation, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited spinal cord ferroptosis following SCI in rats. LSD1 was verified to be a target protein of AF, and AF could concentration-dependently downregulate LSD1 expression in injured spinal cords in vivo and LPS-induced BV-2 cells in vitro. In addition, AF not only inhibited ferroptosis through reducing lipid peroxidase and iron levels and regulating ferroptosis-related proteins, but also inhibited microglial activation and reduced pro-inflammatory cytokines production in LPS-induced BV-2 cells; however, these changes were partly counteracted by LSD1 overexpression. AF could reduce microglial activation and ferroptosis, attenuate neuroinflammation, and improve functional recovery following SCI by downregulating LSD1, providing novel therapeutic strategies for the treatment of SCI.

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阿比福林通过调节 LSD1 介导的微胶质细胞活化和铁凋亡减轻脊髓损伤后的神经炎症并改善功能恢复
脊髓损伤(SCI)是一种严重、持续时间长且不可逆的损伤,治疗方法很少。阿比福林(AF)具有强大的药效学特性,对神经炎症有保护作用。然而,目前还没有研究对阿比福林在脊髓损伤后的神经保护作用进行研究。大鼠接受椎板切除术以建立 SCI 动物模型,并接受 AF(20 毫克/千克和 40 毫克/千克)治疗。进行行为实验以评估 AF 对大鼠 SCI 后运动功能的影响。采用血红素-伊红(HE)染色、Nissl染色和普鲁士蓝染色分别观察组织学变化、神经元损伤和铁沉积。透射电子显微镜观察脊髓组织的超微结构。采用免疫荧光法检测神经元和小胶质细胞。酶联免疫吸附试验检测细胞因子的产生。用 Western 印迹法检测铁突变相关蛋白的表达水平。用 LPS 诱导小胶质细胞 BV-2 以模拟神经炎症状态。细胞活力通过 CCK-8 检测法进行评估,脂质过氧化物酶水平通过 C11 BODIPY 581/591 染色法进行测量。利用分子对接技术证实了AF与LSD1之间的关系。AF改善了大鼠脊髓损伤后的运动功能恢复。同时,AF可减轻神经元凋亡和小胶质细胞活化,减少促炎细胞因子的产生和铁的积累,抑制脊髓损伤后的脊髓铁沉着。经证实,LSD1是AF的靶蛋白,AF能浓度依赖性地下调LSD1在体内损伤脊髓和体外LPS诱导的BV-2细胞中的表达。此外,AF不仅能通过降低脂质过氧化物酶和铁的水平以及调节铁变态反应相关蛋白来抑制铁变态反应,还能抑制LPS诱导的BV-2细胞的小胶质细胞活化并减少促炎细胞因子的产生;然而,这些变化在一定程度上被LSD1的过表达所抵消。AF可以通过下调LSD1来减少小胶质细胞活化和铁突变,减轻神经炎症,改善脊髓损伤后的功能恢复,为治疗脊髓损伤提供了新的治疗策略。
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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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