大鼠前部缺血性视神经病变模型的建立及视神经损伤的动态观察
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摘要
目的
1、建立大鼠前部缺血性视神经病变(anterior ischemic optic neuropathy, AION)模型。
2、探讨AION模型大鼠视神经损伤随时间的动态变化趋势。
3、初步了解外源性神经生长因子(nerve growth factor, NGF)对AION模型大鼠视神经损伤的影响。
方法
1、应用光动力方法制备大鼠AION模型(倍频532nm激光,孟加拉玫瑰红作为光敏剂),以右眼为实验眼(n=23)；单纯激光组大鼠不注射光敏剂、仅激光照射右眼视盘(11=11)；正常对照组大鼠无任何处理(n=13)。借助眼底镜检查、眼底荧光素血管造影,观察AION模型大鼠眼底形态变化；通过HE染色、透射电镜检查,观察大鼠视神经及视网膜的组织病理学表现；采用经上丘荧光金逆行标记法,了解AION导致的RGCs损伤的分布特点。
2、将大鼠随机分为5组：正常对照组(n=10)、模型1周组(n=12)、2周组(n=13)、4周组(n=15)及8周组(n=15)。借助经上丘荧光金逆行标记法、HE染色技术,观察AION模型建立1周、2周、4周、8周后大鼠RGCs的密度及存活率的变化。同时,通过大鼠视神经半薄切片甲苯胺蓝染色,了解不同时间点视神经轴突损伤情况。
3、将大鼠随机分为3组：NGF干预组(n=10)、生理盐水组(n=10)、未干预模型组(n=8)。NGF干预组大鼠分别于损伤后12小时、4天、10天,玻璃体腔注射外源性NGF (2μg/4μL);生理盐水组大鼠在相同时间点玻璃体腔注射等量生理盐水；未干预组大鼠在损伤后不做其他处理。比较4周后各组大鼠的RGCs存活情况及视神经轴突损害的程度。
结果
1、大鼠AION模型建立后,第3天视盘明显水肿,1周后视盘水肿基本消退。眼底荧光素血管造影早期视盘、脉络膜局灶性充盈不良。视神经纵切片HE染色显示模型建立后第3天大鼠视神经水肿、空泡变性,视盘周围局限性视网膜脱离；4周后视神经萎缩,细胞增生明显。电镜下可见第3天模型组大鼠视神经轴突肿胀,部分髓鞘解体；4周后,轴突明显丢失,伴反应性胶质化。视网膜切片HE染色示4周后神经纤维层明显变薄、RGCs凋亡,而视网膜内、外核层无明显变化。荧光金逆行标记显示模型组大鼠RGCs密度明显降低；RGCs损伤呈区域性,以激光照射区附近为重。
2、正常对照组大鼠与AION模型1周组、2周组、4周组及8周组右眼RGCs密度分别为2273±219个/mm2,2075±120个/mm2,1783±143个/mm2,1330±169个/mm2,869±301个/mm2,组间比较显示各组RGCs密度之间的差异均有统计学意义(P<0.05)。上述五组大鼠RGCs存活率分别为99.99%±3.4%,91.8%±2.9%,72.6%±5.7%,54.4%±7.0%,37.5%±13.0%,组间比较显示各组RGCs存活率之间的差异均有统计学意义(P<0.05)。缺血损伤后2周内大鼠RGCs存活率下降相对缓慢；之后RGCs存活率迅速降低,此过程至少持续到第8周。甲苯胺蓝染色显示AION损伤1周后,大鼠视神经即有明显轴突丢失,并逐渐进展；轴突损害以视神经中央部为重；晚期视神经胶质瘢痕明显。
3、NGF干预组大鼠RGCs密度大于生理盐水组及未干预模型组(1447±70个/mm2vs.1298±97个/mm2,1447±70个/mm2vs.1313±153个/mm2；P<0.05)。NGF干预组大鼠RGCs的存活率也明显高于生理盐水组及未干预模型组(62.0%±2.8%vs.53.3%±5.1%,62.0%±2.8%vs.52.3%±7.9%;P<0.05)。NGF干预组大鼠视神经存在明显的轴突丢失及反应性胶质增生。
结论
1、本实验制备的大鼠AION模型与人眼非动脉炎性前部缺血性视神经病变在形态学及组织病理学改变方面有一定的相似性,可以用于后续实验。
2、AION模型大鼠RGCs的损伤相对滞后,并且持续时间长。这期间是神经保护干预的良好时机,有利于挽救有潜在损伤的RGCs。
3、初步研究显示玻璃体腔注射外源性NGF有一定的神经保护作用。
Objective
1. To establish a rat model of anterior ischemic optic neuropathy (rAION).
2. To qualitatively and quantitatively evaluate the time-course of optic nerve (ON) damage in rAION model.
3. To investigate the neuroprotective effects of intravitreally administered nerve growth factor (NGF) on neuronal degeneration in rAION model.
Methods
1. rAION was induced by directly illuminating the ON of the right eye with532nm green laser, after intravenous infusion with the photosensitizing agent Rose Bengal (RB)(n=23). Sham laser treatment consisted of illuminating the ON region with a laser without RB injection(n=11); Rats in normal control group underwent no intervention (n=13). Effect of rAION on the appearance of ON and retina was observed with funduscope and fundus fluorescein angiography (FFA). Hematoxylin and eosin (H&E) staining and transmission electron microscopy were performed to assess rAION-indeced histologic changes in the retina and ON. After labeling RGCs by stereotactic injections of3%FluoroGold (FG) into the superior colliculus, the animals were sacrificed, and RGCs were counted on retinal flat mounts in a masked fashion.
2. The rats were randomly divided into five groups:1-week (n=12),2-week (n=13),4-week (n=15),8-week (n=15) model group and the normal control group (n=10). Animals undergoing AION were sacrificed on7,14,28or56days post-injury. The density of RGCs was calculated by morphometric measurement with FG labeling. The RGC survival rate was defined as ratio of RGC density of right eye/left eye. Semithin sections of ON were stained with toluidine blue for evaluation of axonal degeneration.
3. The rats were randomly divided into three groups:NGF treatment group (n=10), normal saline (NS) treatment group (n=10), and untreated group (n=8). Rats either received exogenous NGF (intravitreal injections,2μg/4μL) or NS12hours,4days, and10days after the modeling. Rats were euthanized at4weeks post-infarct. The number of surviving RGCs was measured by means of RGC staining using retrograde labeling of FG. Toluidine blue staining were performed in the semithin section of ON to identify axonal degeneration in NGF-treated rats.
Results
1. In the rAION-induced eyes, the optic disc was extremely swollen3days after photodynamic therapy. ON edema resolved on day7after induction. The focal filling defect of choroid and optic disc was observed during the early phase of FFA. H&E-stained longitudinal ON sections of rAION revealed peripapillary retinal detachment and vacuolar degeneration corresponded to swollen axons on day3after induction, and optic disc atrophy4weeks after the modeling. Ultrastructural study showed axonal edema and collapsed sheaths in the ischemic optic nerve3days after induction. Four weeks later, there were extensive axonal loss and severe glial scar, accompanied with a reduction of retinal nerve fiber layer thickness and RGC death in large numbers. Meanwhile, no obvious degenerative change was observed in the inner and outer nuclear layers. Retrograde labeling with FG revealed that rAION resulted in regional RGC loss.
2. The density of labeled RGCs was2273±219cells/mm2in control group,2075±120cells/mm2in1-week group,1783±143cells/mm2in2-week group,1330±169cells/mm2in4-week group,869±301cells/mm2in8-week group, respectively; There were significant differences between all pairs of groups(P<0.05, respectively). The survival rate of RGCs was99.9%±3.4%,91.8%±2.9%,72.6%±5.7%,54.4%±7.0%,37.5%±13.0%, respectively; There were significant differences between all pairs of groups(P<0.05, respectively). During the2-week period closely after ischemic injury, RGCs death was a relatively slow process. Thereafter, the number of apoptotic RGCs rapidly increased, which lasted at least for6weeks. Toluidine blue staining of semithin sections of the ON revealed significant demyelination1week after ischemic damage. Progressive axonal degeneration existed for several weeks, which mainly affected the central region of the optic nerve with extensive reactive gliosis.
3. The density of RGCs in NGF-treated rats was1447±70cells/mm2(P<0.05, compared with the NS-treated group,1298±97cells/mm2; P<0.05, compared with the untreated ischemic group,1313±153cells/mm2). Correspondingly, the survival rate of RGCs was significantly higher in the NGF-treated rats than in the NS-treated and the untreated groups(62.0%±2.8%vs.53.3%±5.1%,62.0%±2.8%vs.52.3%±7.9%; both P<0.05). There was obvious axonal loss and glial scar in NGF-treated rats, similar to what happened in untreated ischemic rats.
Conclusions
1. The findings of the rAION model resemble the histologic and physiologic defects seen in human nonarteritic anterior ischemic optic neuropathy. Therefore, rAION model in this study is appropriate for the following research.
2. rAION results in later RGC death. The extended period of cell death after rAION induction is much more longer than previously recognized, when neuroprotective treatment may rescue damaged RGCs.
3. Exogenous NGF has neuroprotective effect on rAION in our pilot study.
1、建立大鼠前部缺血性视神经病变(anterior ischemic optic neuropathy, AION)模型。
2、探讨AION模型大鼠视神经损伤随时间的动态变化趋势。
3、初步了解外源性神经生长因子(nerve growth factor, NGF)对AION模型大鼠视神经损伤的影响。
方法
1、应用光动力方法制备大鼠AION模型(倍频532nm激光,孟加拉玫瑰红作为光敏剂),以右眼为实验眼(n=23)；单纯激光组大鼠不注射光敏剂、仅激光照射右眼视盘(11=11)；正常对照组大鼠无任何处理(n=13)。借助眼底镜检查、眼底荧光素血管造影,观察AION模型大鼠眼底形态变化；通过HE染色、透射电镜检查,观察大鼠视神经及视网膜的组织病理学表现；采用经上丘荧光金逆行标记法,了解AION导致的RGCs损伤的分布特点。
2、将大鼠随机分为5组：正常对照组(n=10)、模型1周组(n=12)、2周组(n=13)、4周组(n=15)及8周组(n=15)。借助经上丘荧光金逆行标记法、HE染色技术,观察AION模型建立1周、2周、4周、8周后大鼠RGCs的密度及存活率的变化。同时,通过大鼠视神经半薄切片甲苯胺蓝染色,了解不同时间点视神经轴突损伤情况。
3、将大鼠随机分为3组：NGF干预组(n=10)、生理盐水组(n=10)、未干预模型组(n=8)。NGF干预组大鼠分别于损伤后12小时、4天、10天,玻璃体腔注射外源性NGF (2μg/4μL);生理盐水组大鼠在相同时间点玻璃体腔注射等量生理盐水；未干预组大鼠在损伤后不做其他处理。比较4周后各组大鼠的RGCs存活情况及视神经轴突损害的程度。
结果
1、大鼠AION模型建立后,第3天视盘明显水肿,1周后视盘水肿基本消退。眼底荧光素血管造影早期视盘、脉络膜局灶性充盈不良。视神经纵切片HE染色显示模型建立后第3天大鼠视神经水肿、空泡变性,视盘周围局限性视网膜脱离；4周后视神经萎缩,细胞增生明显。电镜下可见第3天模型组大鼠视神经轴突肿胀,部分髓鞘解体；4周后,轴突明显丢失,伴反应性胶质化。视网膜切片HE染色示4周后神经纤维层明显变薄、RGCs凋亡,而视网膜内、外核层无明显变化。荧光金逆行标记显示模型组大鼠RGCs密度明显降低；RGCs损伤呈区域性,以激光照射区附近为重。
2、正常对照组大鼠与AION模型1周组、2周组、4周组及8周组右眼RGCs密度分别为2273±219个/mm2,2075±120个/mm2,1783±143个/mm2,1330±169个/mm2,869±301个/mm2,组间比较显示各组RGCs密度之间的差异均有统计学意义(P<0.05)。上述五组大鼠RGCs存活率分别为99.99%±3.4%,91.8%±2.9%,72.6%±5.7%,54.4%±7.0%,37.5%±13.0%,组间比较显示各组RGCs存活率之间的差异均有统计学意义(P<0.05)。缺血损伤后2周内大鼠RGCs存活率下降相对缓慢；之后RGCs存活率迅速降低,此过程至少持续到第8周。甲苯胺蓝染色显示AION损伤1周后,大鼠视神经即有明显轴突丢失,并逐渐进展；轴突损害以视神经中央部为重；晚期视神经胶质瘢痕明显。
3、NGF干预组大鼠RGCs密度大于生理盐水组及未干预模型组(1447±70个/mm2vs.1298±97个/mm2,1447±70个/mm2vs.1313±153个/mm2；P<0.05)。NGF干预组大鼠RGCs的存活率也明显高于生理盐水组及未干预模型组(62.0%±2.8%vs.53.3%±5.1%,62.0%±2.8%vs.52.3%±7.9%;P<0.05)。NGF干预组大鼠视神经存在明显的轴突丢失及反应性胶质增生。
结论
1、本实验制备的大鼠AION模型与人眼非动脉炎性前部缺血性视神经病变在形态学及组织病理学改变方面有一定的相似性,可以用于后续实验。
2、AION模型大鼠RGCs的损伤相对滞后,并且持续时间长。这期间是神经保护干预的良好时机,有利于挽救有潜在损伤的RGCs。
3、初步研究显示玻璃体腔注射外源性NGF有一定的神经保护作用。
Objective
1. To establish a rat model of anterior ischemic optic neuropathy (rAION).
2. To qualitatively and quantitatively evaluate the time-course of optic nerve (ON) damage in rAION model.
3. To investigate the neuroprotective effects of intravitreally administered nerve growth factor (NGF) on neuronal degeneration in rAION model.
Methods
1. rAION was induced by directly illuminating the ON of the right eye with532nm green laser, after intravenous infusion with the photosensitizing agent Rose Bengal (RB)(n=23). Sham laser treatment consisted of illuminating the ON region with a laser without RB injection(n=11); Rats in normal control group underwent no intervention (n=13). Effect of rAION on the appearance of ON and retina was observed with funduscope and fundus fluorescein angiography (FFA). Hematoxylin and eosin (H&E) staining and transmission electron microscopy were performed to assess rAION-indeced histologic changes in the retina and ON. After labeling RGCs by stereotactic injections of3%FluoroGold (FG) into the superior colliculus, the animals were sacrificed, and RGCs were counted on retinal flat mounts in a masked fashion.
2. The rats were randomly divided into five groups:1-week (n=12),2-week (n=13),4-week (n=15),8-week (n=15) model group and the normal control group (n=10). Animals undergoing AION were sacrificed on7,14,28or56days post-injury. The density of RGCs was calculated by morphometric measurement with FG labeling. The RGC survival rate was defined as ratio of RGC density of right eye/left eye. Semithin sections of ON were stained with toluidine blue for evaluation of axonal degeneration.
3. The rats were randomly divided into three groups:NGF treatment group (n=10), normal saline (NS) treatment group (n=10), and untreated group (n=8). Rats either received exogenous NGF (intravitreal injections,2μg/4μL) or NS12hours,4days, and10days after the modeling. Rats were euthanized at4weeks post-infarct. The number of surviving RGCs was measured by means of RGC staining using retrograde labeling of FG. Toluidine blue staining were performed in the semithin section of ON to identify axonal degeneration in NGF-treated rats.
Results
1. In the rAION-induced eyes, the optic disc was extremely swollen3days after photodynamic therapy. ON edema resolved on day7after induction. The focal filling defect of choroid and optic disc was observed during the early phase of FFA. H&E-stained longitudinal ON sections of rAION revealed peripapillary retinal detachment and vacuolar degeneration corresponded to swollen axons on day3after induction, and optic disc atrophy4weeks after the modeling. Ultrastructural study showed axonal edema and collapsed sheaths in the ischemic optic nerve3days after induction. Four weeks later, there were extensive axonal loss and severe glial scar, accompanied with a reduction of retinal nerve fiber layer thickness and RGC death in large numbers. Meanwhile, no obvious degenerative change was observed in the inner and outer nuclear layers. Retrograde labeling with FG revealed that rAION resulted in regional RGC loss.
2. The density of labeled RGCs was2273±219cells/mm2in control group,2075±120cells/mm2in1-week group,1783±143cells/mm2in2-week group,1330±169cells/mm2in4-week group,869±301cells/mm2in8-week group, respectively; There were significant differences between all pairs of groups(P<0.05, respectively). The survival rate of RGCs was99.9%±3.4%,91.8%±2.9%,72.6%±5.7%,54.4%±7.0%,37.5%±13.0%, respectively; There were significant differences between all pairs of groups(P<0.05, respectively). During the2-week period closely after ischemic injury, RGCs death was a relatively slow process. Thereafter, the number of apoptotic RGCs rapidly increased, which lasted at least for6weeks. Toluidine blue staining of semithin sections of the ON revealed significant demyelination1week after ischemic damage. Progressive axonal degeneration existed for several weeks, which mainly affected the central region of the optic nerve with extensive reactive gliosis.
3. The density of RGCs in NGF-treated rats was1447±70cells/mm2(P<0.05, compared with the NS-treated group,1298±97cells/mm2; P<0.05, compared with the untreated ischemic group,1313±153cells/mm2). Correspondingly, the survival rate of RGCs was significantly higher in the NGF-treated rats than in the NS-treated and the untreated groups(62.0%±2.8%vs.53.3%±5.1%,62.0%±2.8%vs.52.3%±7.9%; both P<0.05). There was obvious axonal loss and glial scar in NGF-treated rats, similar to what happened in untreated ischemic rats.
Conclusions
1. The findings of the rAION model resemble the histologic and physiologic defects seen in human nonarteritic anterior ischemic optic neuropathy. Therefore, rAION model in this study is appropriate for the following research.
2. rAION results in later RGC death. The extended period of cell death after rAION induction is much more longer than previously recognized, when neuroprotective treatment may rescue damaged RGCs.
3. Exogenous NGF has neuroprotective effect on rAION in our pilot study.
引文
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