Maisonneuve-Rosemont Hospital Research Center and Department of Ophthalmology, University of Montreal, Canada.
Exp Eye Res. 2012 Apr;97(1):31-5. doi: 10.1016/j.exer.2012.02.006. Epub 2012 Feb 16.
Injury to retinal ganglion cell (RGC) axons within the optic nerve causes apoptosis of the soma. We previously demonstrated that in vivo axotomy causes elevation of superoxide anion within the RGC soma, and that this occurs 1-2 days before annexin-V positivity, a marker of apoptosis. Pegylated superoxide dismutase delivery to the RGC prevents the superoxide elevation and rescues the soma. Together, these results imply that superoxide is an upstream signal for apoptosis after axonal injury in RGCs. We then studied metallocorroles, potent superoxide dismutase mimetics, which we had shown to be neuroprotective in vitro and superoxide scavengers in vivo for RGCs. RGCs were retrograde labeled with the fluorescent dye 4Di-10Asp, and then axotomized by intraorbital optic nerve transection. Iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole (Fe(tpfc)(SO(3)H)(2)) (Fe-corrole) was injected intravitreally. Longitudinal imaging of RGCs was performed and the number of surviving RGCs enumerated. There was significantly greater survival of labeled RGCs with Fe-corrole, but the degree of neuroprotection was relatively less than that predicted by their ability to scavenge superoxide-This implies an unexpected complexity in signaling of apoptosis by reactive oxygen species.
视网膜神经节细胞 (RGC) 轴突在视神经内的损伤导致细胞体凋亡。我们之前的研究表明，体内轴突切断会导致 RGC 细胞体中超氧阴离子的升高，而这种情况发生在 annexin-V 阳性（凋亡的标志物）之前 1-2 天。聚乙二醇化超氧化物歧化酶输送到 RGC 可以防止超氧阴离子的升高并挽救细胞体。这些结果表明，超氧阴离子是 RGC 轴突损伤后凋亡的上游信号。然后，我们研究了金属卟啉，一种有效的超氧化物歧化酶模拟物，我们已经证明它在体外具有神经保护作用，并且在体内是 RGC 的超氧阴离子清除剂。用荧光染料 4Di-10Asp 将 RGC 逆行标记，然后通过眶内视神经切断术进行轴突切断。将三价铁 (III) 2,17-双磺基-5,10,15-三（五氟苯基）卟啉 (Fe(tpfc)(SO3H)2) (Fe-卟啉) 眼内注射。对 RGC 进行纵向成像，并对存活的 RGC 数量进行计数。用 Fe-卟啉处理的标记 RGC 存活数明显增加，但神经保护程度低于其清除超氧阴离子的能力所预测的程度 - 这表明活性氧物种凋亡信号的复杂性出人意料。
