Protection by an oral disubstituted hydroxylamine derivative against loss of retinal ganglion cell differentiation following optic nerve crush.
Protection by an oral disubstituted hydroxylamine derivative against loss of retinal ganglion cell differentiation following optic nerve crush.
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DOI：
10.1371/journal.pone.0065966
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Weinreb RN
中科院分区：
文献类型：
--
作者：
Lindsey JD;Duong-Polk KX;Dai Y;Nguyen DH;Leung CK;Weinreb RN
Thy-1是一种在视网膜神经节细胞（RGC）分化过程中表达的细胞表面蛋白。视神经损伤诱导表达Thy-1的RGC数量的进行性损失。这种损失的速度在视神经损伤后的第一周内最快，在随后的几周内较慢。进行这项研究是为了确定口服水溶性N-羟基-2，2，6，6-四甲基哌啶衍生物（OT-440）是否可以防止视神经挤压后Thy-1启动子激活的丧失，以及这种作用是否针对早期的快速期或后期缓慢期。使用蓝光共聚焦扫描激光检眼镜（bCSL 0）对在Thy-1启动子控制下表达青色荧光蛋白的小鼠（Thy 1-CFP小鼠）的视网膜进行成像。然后，这些小鼠接受口服OT-440，OT-440在奶油干酪中制备或溶于水或普通载体中，持续两周，并在单侧视神经挤压之前再次成像。治疗和每周影像学检查持续四周以上。在每个时间点以掩蔽方式成像的相同限定的视网膜区域中对荧光神经元进行计数。当直接比较每个时间点的计数时，在视神经挤压后1、2、3和4周，在每个时间点，接受OT-440奶油干酪的动物中的荧光细胞数量比相应的对照动物多8%、27%、52%和60%。当载体为水时，获得了类似的结果。速率分析表明，对于奶油干酪载体研究和水载体研究，OT-440的保护作用在前两周内最大，并在压碎后的后两周内维持。由于bCSL 0检测到的大多数荧光细胞是RGC，这些发现表明口服OT-440可以防止或延迟视神经损伤后RGC中发生的早期退行性反应。
Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy-2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury.
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