Liu Lin, Li Dan-Yang, Zhang Long-Qing, Gao Shao-Jie, Song Fan-He, Wu Jia-Yi, Zhou Ya-Qun, Liu Dai-Qiang, Mei Wei
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Mol Pain. 2025 Jan-Dec;21:17448069251348778. doi: 10.1177/17448069251348778. Epub 2025 May 30.
Cancer-induced bone pain (CIBP) is a debilitating complication with few effective treatments. Microglial activation contributes to the progression of CIBP. 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor, could inhibit microglial activation. Its effect on CIBP remains unclear. This study aims to investigate the role of 2-DG in CIBP mice and underlying mechanisms.
In this research, we established a CIBP mouse model by injecting Lewis lung cancer (LLC) cells into the bone marrow of the femur. Relevant pain behaviors were assessed by measuring the paw withdrawal threshold and spontaneous hind limb lifting. Additionally, the glycolysis inhibitor 2-DG was intrathecally administered to treat CIBP in mice. Western blotting and immunofluorescence techniques were employed to analyze microglial activation and M1/M2 phenotype markers in the spinal cord.
Our findings demonstrated significant microglial activation and polarization toward the M1 phenotype in the spinal cord of CIBP mice. Intrathecal administration of 2-DG effectively alleviated pain-related behaviors in CIBP mice. Furthermore, this treatment suppressed microglial activation and M1 polarization, while significantly restoring levels of the M2 phenotype. Additionally, 2-DG attenuated the production of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while boosting the secretion of the anti-inflammatory factor (IL-10) in the spinal cord of CIBP mice. Notably, 2-DG effectively suppresses microglia activation and M1 polarization in LPS + IFN-γ-induced BV-2 cells by downregulating CD86, iNOS expression, TNF-α, IL-1β, IL-6 levels while upregulating Arg-1, CD206 expression and IL-10 level.
These results suggest that 2-DG ameliorates mechanical allodynia, spontaneous pain and neuroinflammation in the spinal cord of CIBP mice by promoting the transition from the M1 phenotype to the M2 phenotype. This study may provide a novel strategy for the treatment of CIBP.
癌症诱发的骨痛（CIBP）是一种使人衰弱的并发症，有效治疗方法很少。小胶质细胞激活促进CIBP的进展。2-脱氧-D-葡萄糖（2-DG），一种糖酵解抑制剂，可抑制小胶质细胞激活。其对CIBP的影响尚不清楚。本研究旨在探讨2-DG在CIBP小鼠中的作用及潜在机制。
在本研究中，我们通过将Lewis肺癌（LLC）细胞注射到股骨骨髓中建立了CIBP小鼠模型。通过测量爪部退缩阈值和自发后肢抬起评估相关疼痛行为。此外，鞘内注射糖酵解抑制剂2-DG来治疗小鼠的CIBP。采用蛋白质免疫印迹法和免疫荧光技术分析脊髓中小胶质细胞激活及M1/M2表型标志物。
我们的研究结果表明，CIBP小鼠脊髓中小胶质细胞显著激活并向M1表型极化。鞘内注射2-DG有效减轻了CIBP小鼠的疼痛相关行为。此外，该治疗抑制了小胶质细胞激活和M1极化，同时显著恢复了M2表型水平。此外，2-DG减弱了CIBP小鼠脊髓中促炎因子如肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的产生，同时促进了抗炎因子（IL-10）的分泌。值得注意的是，2-DG通过下调CD86、诱导型一氧化氮合酶（iNOS）表达、TNF-α、IL-1β、IL-6水平，同时上调精氨酸酶-1（Arg-1）、CD206表达和IL-10水平，有效抑制脂多糖（LPS）+干扰素-γ（IFN-γ）诱导的BV-2细胞中小胶质细胞激活和M1极化。
这些结果表明，2-DG通过促进从M1表型向M2表型的转变，改善了CIBP小鼠脊髓中的机械性异常性疼痛、自发疼痛和神经炎症。本研究可能为CIBP的治疗提供一种新策略。
