Tezel Gülgün, Yang Xiangjun, Yang Junjie, Wax Martin B
Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Boulevard, Louisville, KY 40202, USA.
Brain Res. 2004 Jan 23;996(2):202-12. doi: 10.1016/j.brainres.2003.10.029.
To assess the specific role of tumor necrosis factor (TNF) death receptor signaling in the induction of retinal ganglion cell (RGC) death, optic nerves of mice deficient for TNF receptor-1 (TNF-R1-/-) and control mice (C57BL/6J) were unilaterally subjected to crush injury. Counts of RGCs and their axons 6 weeks after the injury demonstrated that their loss was significantly less in TNF-R1-/- mice compared to controls. The most prominent decrease in neuronal loss detected in TNF-R1-/- mice was beyond the initial 2-week period after the injury. This time period was correlated with the period of glial activation and increased glial immunolabeling for TNF-alpha in these eyes. No further protection against neuronal loss was detectable in TNF-R1-/- mice treated with D-JNKI1, a specific inhibitor of c-Jun N-terminal protein kinase (JNK). However, anti-JNK treatment of control animals provided a significant protection against neuronal loss during the same secondary degeneration period. Phospho-JNK immunolabeling of RGCs in control mice subjected to optic nerve crush significantly decreased following their treatment with D-JNKI1, and anti-JNK treatment protected RGCs from degeneration in these animals, similar to the lack of TNF-R1. These findings provide evidence that TNF death receptor signaling is involved in the secondary degeneration of RGCs following optic nerve injury, and is associated with JNK signaling. Since secondarily degenerating neurons are viable targets for neuroprotection, inhibition of TNF death receptor signaling may be an effective strategy to protect RGCs in several neurodegenerative injuries.
为评估肿瘤坏死因子（TNF）死亡受体信号传导在诱导视网膜神经节细胞（RGC）死亡中的特定作用，对缺乏TNF受体-1（TNF-R1-/-）的小鼠和对照小鼠（C57BL/6J）的视神经进行单侧挤压损伤。损伤6周后对RGC及其轴突进行计数，结果表明，与对照组相比，TNF-R1-/-小鼠中RGC及其轴突的损失明显更少。在TNF-R1-/-小鼠中检测到的神经元损失最显著的减少发生在损伤后的最初2周之后。这一时期与这些眼睛中胶质细胞激活以及TNF-α的胶质免疫标记增加的时期相关。在用c-Jun氨基末端蛋白激酶（JNK）的特异性抑制剂D-JNKI1处理的TNF-R1-/-小鼠中，未检测到对神经元损失的进一步保护作用。然而，对对照动物进行抗JNK治疗在相同的继发性变性期提供了显著的神经元损失保护作用。用D-JNKI1处理视神经挤压后的对照小鼠，其RGCs中的磷酸化JNK免疫标记显著降低，并且抗JNK治疗保护这些动物中的RGCs免于变性，这与缺乏TNF-R1的情况相似。这些发现提供了证据，表明TNF死亡受体信号传导参与视神经损伤后RGCs的继发性变性，并与JNK信号传导相关。由于继发性变性的神经元是神经保护的可行靶点，抑制TNF死亡受体信号传导可能是在几种神经退行性损伤中保护RGCs的有效策略。
