5th Year, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
J Neurosci Res. 2011 Oct;89(10):1596-604. doi: 10.1002/jnr.22698. Epub 2011 Jun 23.
Thalidomide, an inhibitor of tumor necrosis factor-α (TNF-α) production, has been indicated to be useful for many inflammatory and oncogenic diseases. In the present study, we examined whether thalidomide (50 mg/kg/day, p.o.) has a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity in rats. A morphometric analysis showed that systemic administration of thalidomide protects neural cells in the ganglion cell layer (GCL) in a dose-dependent manner and significantly decreases the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in GCL and in the inner nuclear layer (INL). ELISA showed that thalidomide significantly suppressed the elevation of TNF-α 6 and 24 hr after an NMDA injection. Western blot analysis revealed a significant increase in nuclear factor-κB (NF-κB) p65 level in the retinas treated with NMDA at 24 hr after the injection, but not at 6 or 72 hr. Furthermore, an increase in p-JNK and p-p38 levels was also observed in the retina after NMDA injection. Thalidomide suppressed the increased expressions of NF-κB p65, p-JNK, and p-p38 after NMDA injection. Immunohistochemical analysis showed that thalidomide attenuated NF-κB p65 immunoreactivity in the GCL induced by NMDA treatment. In the NMDA-treated group, translocation of NF-κB p65 from the cytoplasm to the nucleus was detected in TUNEL-positive cells exposed to NMDA treatment. These results suggest new indications for thalidomide against neurodegenerative diseases.
沙利度胺是一种肿瘤坏死因子-α（TNF-α）产生抑制剂，已被证明对许多炎症和致癌性疾病有用。在本研究中，我们检查了沙利度胺（50mg/kg/天，口服）是否对大鼠 N-甲基-D-天冬氨酸（NMDA）诱导的视网膜神经毒性具有保护作用。形态计量学分析表明，沙利度胺的系统给药以剂量依赖性方式保护节细胞层（GCL）中的神经细胞，并显着减少 GCL 和内核层（INL）中末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）阳性细胞的数量。 ELISA 显示沙利度胺显着抑制 NMDA 注射后 6 和 24 小时 TNF-α水平的升高。 Western blot 分析显示，NMDA 注射后 24 小时视网膜中核因子-κB（NF-κB）p65 水平显着增加，但在 6 或 72 小时则没有。此外，在 NMDA 注射后还观察到 JNK 和 p38 水平的升高。沙利度胺抑制了 NMDA 注射后 NF-κB p65、p-JNK 和 p-p38 的表达增加。免疫组织化学分析显示，沙利度胺减弱了 NMDA 处理诱导的 GCL 中 NF-κB p65 的免疫反应性。在 NMDA 处理组中，在 NMDA 处理的 TUNEL 阳性细胞中检测到 NF-κB p65 从细胞质向细胞核易位。这些结果为沙利度胺治疗神经退行性疾病提供了新的适应症。
