Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
Cell Death Dis. 2018 May 1;9(5):460. doi: 10.1038/s41419-018-0543-8.
Spinal cord injury (SCI) induces severe and long-lasting neurological disability. Accumulating evidence has suggested that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults and deficits in the central nervous system. In the present study, we assessed the effect of the class I HDAC inhibitor CI-994 in a mouse model of SCI. Following SCI, mice were treated with either dimethyl sulfoxide (control vehicle) or 1, 10, or 30 mg/kg CI-994. Level of acetylated histone H3 expression was increased in the motor cortex and spinal cord of 10 mg/kg CCI-994-treated mice after SCI. CI-994 increased histone H3 acetylation in the myeloperoxidase-positive neutrophils and CD68-positive microglia/macrophages in the spinal cord. Although it did not appear to contribute to corticospinal tract axonal reorganization, intraperitoneal injection of CI-994 promoted behavioral recovery following SCI. Furthermore, administration of CI-994 suppressed neutrophil accumulation, inflammatory cytokine expressions, and neuronal loss as early as 3 days following injury. Thus, our findings indicate that HDAC inhibitors may improve functional recovery following SCI, especially during the early stages of the disease.
脊髓损伤（SCI）会导致严重且持久的神经功能障碍。越来越多的证据表明，组蛋白去乙酰化酶（HDAC）抑制剂对中枢神经系统的各种损伤和缺陷具有神经保护作用。在本研究中，我们评估了 I 类 HDAC 抑制剂 CI-994 在 SCI 小鼠模型中的作用。SCI 后，用二甲基亚砜（对照载体）或 1、10 或 30mg/kg CI-994 处理小鼠。SCI 后，10mg/kg CCI-994 处理的小鼠大脑皮质和脊髓中的乙酰化组蛋白 H3 表达水平增加。CI-994 增加了脊髓中髓过氧化物酶阳性中性粒细胞和 CD68 阳性小胶质细胞/巨噬细胞中的组蛋白 H3 乙酰化。虽然它似乎不会促进皮质脊髓束轴突重组，但腹腔内注射 CI-994 可促进 SCI 后的行为恢复。此外，CI-994 的给药早在损伤后 3 天即可抑制中性粒细胞聚集、炎症细胞因子表达和神经元丢失。因此，我们的研究结果表明，HDAC 抑制剂可能改善 SCI 后的功能恢复，尤其是在疾病的早期阶段。
