Arctiin Mitigates Neuronal Injury by Modulating the P2X7R/NLPR3 Inflammasome Signaling Pathway.

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-17 DOI:10.1007/s10753-024-02117-z
Guang-Nan Jin, Yu Wang, Yi-Ming Liu, Yu-Nan Lu, Jing-Mei Lu, Jing-He Wang, Jing-Wen Ma, Yan-Zhu Quan, Hong-Yan Gao, Yue-Xian Cui, Xiang Xu, Lian-Xun Piao
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Abstract

Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.

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Arctiin 通过调节 P2X7R/NLPR3 炎症体信号通路减轻神经元损伤
抑郁症是全球公认的主要致残原因,其发病机制与神经炎症和神经元损伤密切相关。八角茴香苷(ARC)是八角茴香的主要生物活性成分,具有多种药理活性,如抗炎和神经保护作用。先前的研究结果强调了 ARC 能够通过抑制小胶质细胞的过度活化来减轻抑郁症,从而减少小鼠的神经炎症反应和皮层神经元损伤,在此基础上,本研究通过考察 ARC 对抑郁症患者海马神经元损伤的影响,深入探讨了 ARC 的治疗潜力。本研究利用慢性不可预测轻度应激(CUMS)诱导的小鼠抑郁模型和皮质酮(CORT)刺激的PC12细胞神经元损伤模型,通过尼氏染色、免疫组化、Western印迹、ELISA、乳酸脱氢酶测定、集落形成测定、免疫荧光染色和分子对接等技术,揭示了ARC神经保护作用的机制。研究结果表明,ARC 不仅能减轻 CUMS 暴露小鼠海马神经病理学损伤并降低血清 CORT 水平,还能增强细胞活性,同时减少 CORT 刺激的 PC12 细胞中乳酸脱氢酶的释放。ARC 通过抑制 P2X7 受体(P2X7R)/类 NOD 受体家族含吡啶域 3(NLRP3)炎性组信号通路的过度激活,减轻了神经炎症反应和神经元凋亡,其效果与 A438079(P2X7R 拮抗剂)相似。有趣的是,预处理 A438079 会阻断 ARC 的神经保护作用。计算机模型预测,ARC和A438079都与P2X7R有很强的结合力,而且它们的结合位点相同。这些结果表明,ARC可能通过与P2X7R结合发挥神经保护作用,从而抑制P2X7R/NLRP3炎性体信号通路。
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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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