Sophie and Arthur Brody Optic Nerve Laboratory, Hamilton Glaucoma Center, University of California San Diego, La Jolla, California 92037, USA.
Invest Ophthalmol Vis Sci. 2011 Apr 27;52(5):2837-43. doi: 10.1167/iovs.09-5010. Print 2011 Apr.
To determine whether acute intraocular pressure (IOP) elevation alters dynamin-related protein 1 (Drp1) as well as whether a selective inhibitor of Drp1, mdivi-1, can block apoptotic cell death and subsequently increase retinal ganglion cell (RGC) survival in ischemic mouse retina.
C57BL/6 mice received injections of mdivi-1 (50 mg/kg) or vehicle, and then transient retinal ischemia was induced by acute IOP elevation. RGC survival was measured after FluoroGold labeling. Drp1 and glial fibrillary acidic protein (GFAP) protein expression and distribution were assessed at 12 hours after ischemia-reperfusion by Western blot and immunohistochemistry. Apoptotic cell death was assessed by TUNEL staining.
Drp1 and GFAP protein expression was significantly increased in the early neurodegenerative events (within 12 hours) of ischemic mouse retina. Mdivi-1 treatment blocked apoptotic cell death in ischemic retina, and significantly increased RGC survival at 2 weeks after ischemia. In the normal mouse retina, Drp1 is expressed in the ganglion cell layer (GCL) as well as the inner plexiform layer, the inner nuclear layer (INL), and the outer plexiform layer (OPL). In the GCL, Drp1 immunoreactivity was strong in RGCs. While Drp1 protein expression was increased in the GCL of vehicle-treated ischemic retina at 12 hours. Mdivi-1 treatment did not change this increase of Drp1 protein expression but significantly decreased GFAP protein expression.
These findings suggest that altered Drp1 activity after acute IOP elevation may be an important component of a biochemical cascade leading to RGC death in ischemic retina.
确定急性眼内压（IOP）升高是否会改变与动力相关蛋白 1（Drp1），以及 Drp1 的选择性抑制剂 mdivi-1 是否可以阻断细胞凋亡并随后增加缺血性鼠视网膜中的神经节细胞（RGC）存活。
C57BL/6 小鼠接受 mdivi-1（50mg/kg）或载体注射，然后通过急性 IOP 升高诱导短暂性视网膜缺血。用 FluoroGold 标记后测量 RGC 存活。通过 Western blot 和免疫组织化学在缺血再灌注后 12 小时评估 Drp1 和胶质纤维酸性蛋白（GFAP）蛋白表达和分布。通过 TUNEL 染色评估细胞凋亡。
在缺血性鼠视网膜的早期神经退行性事件（12 小时内）中，Drp1 和 GFAP 蛋白表达明显增加。mdivi-1 治疗阻断了缺血性视网膜中的细胞凋亡，并在缺血后 2 周显著增加了 RGC 存活。在正常鼠视网膜中，Drp1 在神经节细胞层（GCL）以及内丛状层、内核层（INL）和外丛状层（OPL）中表达。在 GCL 中，Drp1 免疫反应性在 RGC 中较强。虽然在缺血性视网膜中，载体处理的 Drp1 蛋白表达在 GCL 中在 12 小时时增加，但 mdivi-1 处理并未改变这种 Drp1 蛋白表达的增加，但明显降低了 GFAP 蛋白表达。
这些发现表明，急性 IOP 升高后 Drp1 活性的改变可能是导致缺血性视网膜中 RGC 死亡的生化级联反应的重要组成部分。
