Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
PLoS One. 2013 Aug 21;8(8):e73640. doi: 10.1371/journal.pone.0073640. eCollection 2013.
High mobility group box-1 (HMGB1) is associated with the pathogenesis of inflammatory diseases. A previous study reported that intravenous injection of anti-HMGB1 monoclonal antibody significantly attenuated brain edema in a rat model of stroke, possibly by attenuating glial activation. Peripheral nerve injury leads to increased activity of glia in the spinal cord dorsal horn. Thus, it is possible that the anti-HMGB1 antibody could also be efficacious in attenuating peripheral nerve injury-induced pain. Following partial sciatic nerve ligation (PSNL), rats were treated with either anti-HMGB1 or control IgG. Intravenous treatment with anti-HMGB1 monoclonal antibody (2 mg/kg) significantly ameliorated PSNL-induced hind paw tactile hypersensitivity at 7, 14 and 21 days, but not 3 days, after ligation, whereas control IgG had no effect on tactile hypersensitivity. The expression of HMGB1 protein in the spinal dorsal horn was significantly increased 7, 14 and 21 days after PSNL; the efficacy of the anti-HMGB1 antibody is likely related to the presence of HMGB1 protein. Also, the injury-induced translocation of HMGB1 from the nucleus to the cytosol occurred mainly in dorsal horn neurons and not in astrocytes and microglia, indicating a neuronal source of HMGB1. Markers of astrocyte (glial fibrillary acidic protein (GFAP)), microglia (ionized calcium binding adaptor molecule 1 (Iba1)) and spinal neuron (cFos) activity were greatly increased in the ipsilateral dorsal horn side compared to the sham-operated side 21 days after PSNL. Anti-HMGB1 monoclonal antibody treatment significantly decreased the injury-induced expression of cFos and Iba1, but not GFAP. The results demonstrate that nerve injury evokes the synthesis and release of HMGB1 from spinal neurons, facilitating the activity of both microglia and neurons, which in turn leads to symptoms of neuropathic pain. Thus, the targeting of HMGB1 could be a useful therapeutic strategy in the treatment of chronic pain.
高迁移率族蛋白 B1（HMGB1）与炎症性疾病的发病机制有关。先前的研究报道，静脉注射抗 HMGB1 单克隆抗体可显著减轻大鼠中风模型中的脑水肿，可能通过减轻神经胶质细胞的激活。周围神经损伤导致脊髓背角中的神经胶质细胞活性增加。因此，抗 HMGB1 抗体也可能有效减轻周围神经损伤引起的疼痛。坐骨神经部分结扎（PSNL）后，大鼠用抗 HMGB1 或对照 IgG 治疗。静脉注射抗 HMGB1 单克隆抗体（2mg/kg）可显著改善 PSNL 后 7、14 和 21 天的后爪触觉过敏，但结扎后 3 天无作用，而对照 IgG 对触觉过敏无影响。PSNL 后 7、14 和 21 天，脊髓背角 HMGB1 蛋白表达明显增加；抗 HMGB1 抗体的疗效可能与 HMGB1 蛋白的存在有关。此外，HMGB1 从核到细胞质的损伤诱导易位主要发生在背角神经元中，而不是星形胶质细胞和小胶质细胞中，表明 HMGB1 的神经元来源。PSNL 后 21 天，与假手术侧相比，同侧背角侧星形胶质细胞（胶质纤维酸性蛋白（GFAP））、小胶质细胞（钙结合衔接蛋白分子 1（Iba1））和脊髓神经元（cFos）活性的标志物显著增加。抗 HMGB1 单克隆抗体治疗可显著降低损伤诱导的 cFos 和 Iba1 表达，但不降低 GFAP 表达。结果表明，神经损伤会从脊髓神经元中合成和释放 HMGB1，促进小胶质细胞和神经元的活性，进而导致神经病理性疼痛的症状。因此，靶向 HMGB1 可能是治疗慢性疼痛的一种有用的治疗策略。
