米诺环素在L-谷氨酸诱导的视网膜神经节细胞损伤中的保护作用和分子机制
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摘要
目的：探讨米诺环素在L-谷氨酸诱导的视网膜神经节细胞损伤中的保护作用和分子机制。
方法：体外实验,原代小鼠视网膜神经节细胞体外稳定培养24h后,分为三组：对照组、L-谷氨酸组及L-谷氨酸+米诺环素组,相应干预48h后分别观察各组间神经节细胞的存活率及神经轴突生长的差异。体内实验,将C57BL／6小鼠分为三组：对照组、L-谷氨酸组及L-谷氨酸+米诺环素组。前两组小鼠腹腔内注射生理盐水(对照组,L-谷氨酸组),第三组腹腔内注射米诺环素(L-谷氨酸+米诺环素组,60mg/kg),每天一次,连续7天,第二天时,第一组玻璃体腔内注射生理盐水,后两组小鼠玻璃体腔内注射2ulL-谷氨酸(2mM),诱导视网膜神经节细胞损伤。第八天采用组织免疫荧光法技术和激光共聚焦显微镜观察β3tubulin阳性细胞数及视网膜GFAP蛋白表达以评估视网膜神经节细胞的损伤情况。Real-time PCR和Western blot法分别检测视网膜组织中IFN-γ, IL-1, TNF-α与GFAP与Vimentin的mRNA及蛋白表达水平以初步探讨损伤的分子机制。
结果：体外实验结果显示：与对照组比较,L-谷氨酸组视网膜神经节细胞的存活率明显降低,呈剂量和时间依赖性；神经轴突生长受抑制。米诺环素干预后可明显减轻L-谷氨酸导致的上述效应(P<0.01)。动物实验结果显示,L-谷氨酸组小鼠神网膜神经节细胞数目较对照组小鼠显著减少,视网膜组织中GFAP的表达量明显增加(P<0.01)。米诺环素治疗后可明显改善L-谷氨酸诱导的神经节细胞损伤并明显降低其GFAP的表达(p<0.01)。视网膜组织中IFN-γ、IL-1、NF-α与GFAP与Vimentin的mRNA及蛋白水平在L-谷氨酸组较对照组表达明显增高,而米诺环素可显著降低这些因子的表达。
结论：L-谷氨酸可诱导视网膜神经节细胞损伤、抑制神经轴突生长和上调炎症因子基因与蛋白的表达,而米诺环素具有明显改善L-谷氨酸所导致的视网膜神经细胞损伤的作用。
Objective:To investigate the protective effect and molecular mechanism of minocycline on toxicity of retinal ganglion cells induced by L-glutamate.
Methods:In vitro experiments, primary mouse retinal ganglion cells (RGCs) was isolated and identification from mouse retinal. RGCs were divided into control group, L-glutamate group, and L-glutamate + minocycline group.48hours late, the cell survival rate and nerve axon growth length were observed in each group. In vivo study, C57BL/6 mice were divided into control group, L-glutamate group, and L-glutamate + minocycline group.In the former 2 groups,the mice were daily intraperitoneal injected with saline and the mice in the third group were daily intraperitoneal injected with minocycline (60mg/kg, saline injected in the control group) till day 7.on the 2nd day,mice in the first group were intravitreal injected with saline and mice in the latter 2 groups were intravitreal injected with 2ul L-glutamate (2mM) to construct a toxic damage to retinal ganglion cells animal model.On 8th day,β3 tubulin positive cells and retinal GFAP protein expression were evaluated by tissue immunofluorescence assay. Real-time PCR and Western blot assay were used to detect IFN-y, IL-1, TNF-a and GFAP and Vimentin mRNA and protein expression level in retinal tissues.
Results:Compared with control group, RGCs survival rate in L-glutamate group was significantly reduced with a dose-and time-dependent. In addition, axon growth was inhibited with the treatment of glutamic acid, while these effects were abolished in the minocycline group (P<0.01). Animal study showed that the number of RGCs dramatically decreased,however, expression of GFAP in retinal tissue significantly increased in L-glutamate treated mice, compared to control (P<0.01). Minocycline treatment significantly improved L-glutamate-induced ganglion cell damage and significantly reduce their GFAP expression (p<0.01). Both mRNA and protein expression levels of IFN-y, IL-1, TNF-a and GFAP and Vimentin in retinal tissue of L-glutamic acid group significantly upregulated compared to control(p <0.01), while the minocycline significantly reduces the expression of these factors(p<0.01).
Conclusion:L-glutamic acid can induce retinal ganglion cell damage, inhibit axon growth and increase inflammatory gene and protein expression, but minocycline has a significant improvement in L-glutamate caused by retinal nerve cell damage role.
方法：体外实验,原代小鼠视网膜神经节细胞体外稳定培养24h后,分为三组：对照组、L-谷氨酸组及L-谷氨酸+米诺环素组,相应干预48h后分别观察各组间神经节细胞的存活率及神经轴突生长的差异。体内实验,将C57BL／6小鼠分为三组：对照组、L-谷氨酸组及L-谷氨酸+米诺环素组。前两组小鼠腹腔内注射生理盐水(对照组,L-谷氨酸组),第三组腹腔内注射米诺环素(L-谷氨酸+米诺环素组,60mg/kg),每天一次,连续7天,第二天时,第一组玻璃体腔内注射生理盐水,后两组小鼠玻璃体腔内注射2ulL-谷氨酸(2mM),诱导视网膜神经节细胞损伤。第八天采用组织免疫荧光法技术和激光共聚焦显微镜观察β3tubulin阳性细胞数及视网膜GFAP蛋白表达以评估视网膜神经节细胞的损伤情况。Real-time PCR和Western blot法分别检测视网膜组织中IFN-γ, IL-1, TNF-α与GFAP与Vimentin的mRNA及蛋白表达水平以初步探讨损伤的分子机制。
结果：体外实验结果显示：与对照组比较,L-谷氨酸组视网膜神经节细胞的存活率明显降低,呈剂量和时间依赖性；神经轴突生长受抑制。米诺环素干预后可明显减轻L-谷氨酸导致的上述效应(P<0.01)。动物实验结果显示,L-谷氨酸组小鼠神网膜神经节细胞数目较对照组小鼠显著减少,视网膜组织中GFAP的表达量明显增加(P<0.01)。米诺环素治疗后可明显改善L-谷氨酸诱导的神经节细胞损伤并明显降低其GFAP的表达(p<0.01)。视网膜组织中IFN-γ、IL-1、NF-α与GFAP与Vimentin的mRNA及蛋白水平在L-谷氨酸组较对照组表达明显增高,而米诺环素可显著降低这些因子的表达。
结论：L-谷氨酸可诱导视网膜神经节细胞损伤、抑制神经轴突生长和上调炎症因子基因与蛋白的表达,而米诺环素具有明显改善L-谷氨酸所导致的视网膜神经细胞损伤的作用。
Objective:To investigate the protective effect and molecular mechanism of minocycline on toxicity of retinal ganglion cells induced by L-glutamate.
Methods:In vitro experiments, primary mouse retinal ganglion cells (RGCs) was isolated and identification from mouse retinal. RGCs were divided into control group, L-glutamate group, and L-glutamate + minocycline group.48hours late, the cell survival rate and nerve axon growth length were observed in each group. In vivo study, C57BL/6 mice were divided into control group, L-glutamate group, and L-glutamate + minocycline group.In the former 2 groups,the mice were daily intraperitoneal injected with saline and the mice in the third group were daily intraperitoneal injected with minocycline (60mg/kg, saline injected in the control group) till day 7.on the 2nd day,mice in the first group were intravitreal injected with saline and mice in the latter 2 groups were intravitreal injected with 2ul L-glutamate (2mM) to construct a toxic damage to retinal ganglion cells animal model.On 8th day,β3 tubulin positive cells and retinal GFAP protein expression were evaluated by tissue immunofluorescence assay. Real-time PCR and Western blot assay were used to detect IFN-y, IL-1, TNF-a and GFAP and Vimentin mRNA and protein expression level in retinal tissues.
Results:Compared with control group, RGCs survival rate in L-glutamate group was significantly reduced with a dose-and time-dependent. In addition, axon growth was inhibited with the treatment of glutamic acid, while these effects were abolished in the minocycline group (P<0.01). Animal study showed that the number of RGCs dramatically decreased,however, expression of GFAP in retinal tissue significantly increased in L-glutamate treated mice, compared to control (P<0.01). Minocycline treatment significantly improved L-glutamate-induced ganglion cell damage and significantly reduce their GFAP expression (p<0.01). Both mRNA and protein expression levels of IFN-y, IL-1, TNF-a and GFAP and Vimentin in retinal tissue of L-glutamic acid group significantly upregulated compared to control(p <0.01), while the minocycline significantly reduces the expression of these factors(p<0.01).
Conclusion:L-glutamic acid can induce retinal ganglion cell damage, inhibit axon growth and increase inflammatory gene and protein expression, but minocycline has a significant improvement in L-glutamate caused by retinal nerve cell damage role.
引文
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2 CARNEY S, BUTCHER R A, DAWBORN J K, et al. Minocycline excretion and distribution in relation to renal function in man[J]. Clin Exp Phalmacol Physiol,1974,1(4):299-308.
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4 Bodeutsch N. Thanos S. Migration of phagocytotic ceUs and development of the murine intraretinal microglial network:an in vivo study using fluorescent dyes[J]. Gila,2000,32:91-101
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