Yin-Di Hu, Zhao-Di Wang, Yuan-Fen Yue, Dai Li, Shu-Qing Zhen, Jie-Qiong Ding, Wei Meng, Hai-Li Zhu, Min Xie, Ling Liu
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引用次数: 0
摘要
癌性骨痛(CIBP)的特征是中度至重度疼痛,对患者的日常功能状态和生活质量产生负面影响。当癌细胞转移并在骨髓中生长时,这会激活脊髓中的神经炎症,这在慢性疼痛的产生和持续中起着至关重要的作用。本研究将MRMT - 1大鼠乳腺癌细胞接种于雄性Sprague - Dawley大鼠胫骨髓腔,构建CIBP模型。手术两周后,CIBP大鼠表现出骨结构受损、疼痛敏感性增加和运动协调性受损。CIBP大鼠脊髓神经炎症被激活,表现为广泛的白细胞滤过,细胞因子水平上调和星形胶质细胞活化。组蛋白去乙酰化酶6 (HDAC6)是慢性疼痛的治疗靶点。在腰椎脊髓鞘内注射HDAC6抑制剂tubastatin A (TSA)导致脊髓炎性细胞因子产生减少,抑制脊髓星形胶质细胞活化,降低NOD样受体pyrin结构域3 (NLRP3)炎性体活性。因此,这种作用减轻了自发性疼痛和机械性痛觉过敏,恢复了CIBP大鼠的运动协调能力。免疫沉淀实验表明,TSA治疗降低了HDAC6与NLRP3之间的相互作用。对C6大鼠胶质瘤细胞的细胞研究证实,TSA处理降低了HDAC6和NLRP3的表达。综上所述,本研究结果表明,TSA治疗通过抑制脊髓中HDAC6/NLRP3炎症小体信号通路来缓解癌性骨痛。
Inhibition of HDAC6 alleviates cancer‑induced bone pain by reducing the activation of NLRP3 inflammasome.
Cancer‑induced bone pain (CIBP) is characterized as moderate to severe pain that negatively affects the daily functional status and quality of life of patients. When cancer cells metastasize and grow in bone marrow, this activates neuroinflammation in the spinal cord, which plays a vital role in the generation and persistence of chronic pain. In the present study, a model of CIBP was constructed by inoculating of MRMT‑1 rat breast carcinoma cells into the medullary cavity of the tibia in male Sprague‑Dawley rats. Following two weeks of surgery, CIBP rats exhibited damaged bone structure, increased pain sensitivity and impaired motor coordination. Neuroinflammation was activated in the spinal cords of CIBP rats, presenting with extensive leukocyte filtration, upregulated cytokine levels and activated astrocytes. Histone deacetylase 6 (HDAC6) works as a therapeutic target for chronic pain. The intrathecal injection of the HDAC6 inhibitor tubastatin A (TSA) in the lumbar spinal cord resulted in decreased spinal inflammatory cytokine production, suppressed spinal astrocytes activation and reduced NOD‑like receptor pyrin domain containing 3 (NLRP3) inflammasome activity. Consequently, this effect alleviated spontaneous pain and mechanical hyperalgesia and recovered motor coordination in CIBP rats. It was demonstrated by immunoprecipitation assay that TSA treatment reduced the interaction between HDAC6 and NLRP3. Cell research on C6 rat glioma cells served to verify that TSA treatment reduced HDAC6 and NLRP3 expression. In summary, the findings of present study indicated that TSA treatment alleviated cancer‑induced bone pain through the inhibition of HDAC6/NLRP3 inflammasome signaling in the spinal cord.
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