Retinal neuronal death induced by intraocular administration of a nitric oxide donor and its rescue by neurotrophic factors in rats.
Retinal neuronal death induced by intraocular administration of a nitric oxide donor and its rescue by neurotrophic factors in rats.
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DOI：
10.1167/iovs.02-0471
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发表时间：
2003-04
影响因子：
4.4
通讯作者：
K. Takahata;H. Katsuki;T. Kume;Daisuke Nakata;Ken Ito;Shizuko Muraoka;F. Yoneda;S. Kashii;Y. Honda;A. Akaike
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文献类型：
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作者：
K. Takahata;H. Katsuki;T. Kume;Daisuke Nakata;Ken Ito;Shizuko Muraoka;F. Yoneda;S. Kashii;Y. Honda;A. Akaike
目的观察一氧化氮(NO)供体释放的一氧化氮(NO)对大鼠视网膜的神经毒性作用，探讨神经营养因子对NO损伤视网膜细胞存活的影响。方法向大鼠右眼玻璃体腔注射NO释放化合物N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)乙胺(NOC12)。通过对神经节细胞层(GCL)细胞计数和测量视网膜层厚度来评价NOC12对视网膜神经元的影响以及睫状神经营养因子(CNTF)或脑源性神经营养因子(BDNF)对NOC12所致损伤的神经保护作用。视网膜神经节细胞(RGC)的准确计数也通过荧光示踪剂逆行标记的方法得到确认。结果NOC12暴露眼视网膜损伤的形态计量学分析显示，GCL细胞密度显著降低，内网状层和内核层厚度减少，而外核层厚度无明显变化，且呈剂量依赖性。玻璃体内注射NOC12后，视网膜切片TdT-dUTP末端缺口标记结果显示，NO可诱导细胞凋亡。用荧光示踪剂标记的视网膜节细胞计数表明，NOC12引起的GCL细胞密度的降低反映了视网膜节细胞的丢失。在玻璃体内注射NOC12(400nmoL)前给予CNTF(1微克)或BDNF(1微克)，证明这些营养因子对NO诱导的视网膜神经细胞死亡具有保护作用。结论外源性NO可诱导视网膜神经毒性，提示NO在视网膜退行性疾病中起致病作用。BDNF和CNTF保护视网膜神经元免受NO介导的神经毒性。
PURPOSE To investigate the neurotoxic outcome in the rat retina exposed to nitric oxide (NO) released from an NO donor and to evaluate the effects of neurotrophic factors on the survival of NO-damaged retinal cells. METHODS An NO releasing compound, N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine (NOC 12), was intravitreously injected into a rat's right eye. The influences of NOC 12 on retinal neurons and the neuroprotective effects of ciliary neurotrophic factor (CNTF) or brain-derived neurotrophic factor (BDNF) on NOC 12-mediated damage were estimated by counting cells in the ganglion cell layer (GCL) and by measuring the thickness of retinal layers. The exact count of retinal ganglion cells (RGCs) was also confirmed by means of retrograde labeling with a fluorescent tracer. RESULTS Morphometric analyses of retinal damage in the NOC 12-exposed eyes demonstrated a significant and dose-dependent decrease in cell density in the GCL and a reduction in thickness of the inner plexiform layer and inner nuclear layer, but not of the outer nuclear layer. TdT-dUTP terminal nick-end labeling of retinal sections after intravitreous injection of NOC 12 demonstrated that NO could trigger apoptotic cell death. The counting of the RGCs labeled with a fluorescent tracer suggested that a decrease in GCL cell density induced by NOC 12 reflects a loss in RGCs. Treatment with CNTF (1 microg) or BDNF (1 microg) before the intravitreous injection of NOC 12 (400 nmol) demonstrated that these trophic factors have protective effects against NO-induced neuronal cell death in the retina. CONCLUSIONS Exogenous NO induces retinal neurotoxicity, suggesting that NO plays a pathogenic role in degenerative retinal diseases. BDNF and CNTF protect retinal neurons from NO-mediated neurotoxicity.