通过局部注射多巴胺能神经毒素模拟视网膜神经变性的早期阶段

T. Pavlenko, N. Chesnokova, O. Beznos, A. V. Grigoryev, T. D. Okhotsimskaya, N. N. Shikareva
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On the 7th day after an injection of 0.25 mg 6-OHDA, we used ELISA to measure dopamine concentration in retinal homogenates, while on the 14th day after an injection of 0.5 mg 6-OHDA, the concentrations of dopamine, norepinephrine, TNF-a and endothelin-1 were measured by the same method. Results. On the 7th day after a 0,25 mg injection of neurotoxine, we revealed a decrease of dopamine in the retina (0.043 ± 0.130 pg/mg protein compared with 0.10 ± 0,03 pg/mg protein in the controls, р < 0.01). On the 14th day, dopamine and norepinephrine levels showed a fourfold increase (р < 0.05). An injection of 0.5 mg of 6-OHDA caused a threefold increase of dopamine (р < 0.05) and a fivefold increase of norepinephrine (р < 0.01) concentration in comparison with the controls. On the 14th day, endotheline-1 level was 65 % higher than in the controls after a 0.25 mg 6-OHDA injection (р < 0.01) and 45 % higher after a 0,5 mg injection (р<0.05). 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引用次数: 0

摘要

目的:通过在玻璃体内注射多巴胺能神经毒素,建立视网膜神经变性早期阶段的模型。材料与方法实验对象为 20 只栗鼠兔。实验组接受 0.1 毫升 6-羟基多巴胺(6-OHDA)(含 0.9%氯化钠和 0.5%抗坏血酸)的玻璃体内注射,其中含有 0.25 或 0.5 毫克 6-OHDA。对照组注射 0.1 毫升不含神经毒素的氯化钠-抗坏血酸溶液。在注射后的第 7 天和第 14 天,对眼压、瞳孔光反应和眼血流量进行估计,并检查眼底。在注射0.25毫克6-OHDA后的第7天,我们用ELISA法测定视网膜匀浆中多巴胺的浓度;在注射0.5毫克6-OHDA后的第14天,我们用同样的方法测定多巴胺、去甲肾上腺素、TNF-a和内皮素-1的浓度。结果显示在注射 0.25 毫克神经毒素后的第 7 天,我们发现视网膜中的多巴胺减少(0.043 ± 0.130 pg/mg 蛋白,对照组为 0.10 ± 0.03 pg/mg 蛋白,р < 0.01)。第 14 天,多巴胺和去甲肾上腺素水平增加了四倍(р < 0.05)。与对照组相比,注射 0.5 毫克 6-OHDA 会导致多巴胺浓度增加三倍(р < 0.05),去甲肾上腺素浓度增加五倍(р < 0.01)。第14天,注射0.25毫克6-OHDA后,内皮素-1水平比对照组高65%(р < 0.01),注射0.5毫克后比对照组高45%(р < 0.05)。与此同时,TNF-α水平分别增加了43%(р < 0.05)和20%(р < 0.05)。我们还发现,注射神经毒素后,眼压变化呈剂量依赖性,瞳孔光反应紊乱,眼血流量减少。结论每只眼睛静脉注射 0.25 或 0.5 毫克的多巴胺能神经毒素 6-OHDA 会导致神经炎症和血管紊乱,而这正是神经变性的主要致病途径。要模拟其早期阶段,0.25 毫克的剂量更可取,因为它导致的功能紊乱较不明显。后一种模型有助于研究视网膜神经变性的发病机制,寻找早期诊断和预后标志物,以及评估治疗效果。
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Modelling of the early stage of retinal neurodegeneration via a topical injection of dopaminergic neurotoxin
Purpose: to develop a model of the early stage of retinal neurodegeneration via an intravitreal injection of the dopaminergic neurotoxin. Material and methods. The experiment was carried out on 20 Chinchilla rabbits. The experimental groups received intravitreal injection of 0.1 ml of 6-hydroxydopamine (6-OHDA) in NaCl 0.9 % with 0.5 % ascorbate, containing 0.25 or 0.5 mg 6-OHDA. The control group received injections of 0.1 ml of NaCl-ascorbate solution without neurotoxin. On the 7th and the 14th days after the injection, intraocular pressure (IOP), pupillary light reaction and ocular blood flow were estimated and the fundus was examined. On the 7th day after an injection of 0.25 mg 6-OHDA, we used ELISA to measure dopamine concentration in retinal homogenates, while on the 14th day after an injection of 0.5 mg 6-OHDA, the concentrations of dopamine, norepinephrine, TNF-a and endothelin-1 were measured by the same method. Results. On the 7th day after a 0,25 mg injection of neurotoxine, we revealed a decrease of dopamine in the retina (0.043 ± 0.130 pg/mg protein compared with 0.10 ± 0,03 pg/mg protein in the controls, р < 0.01). On the 14th day, dopamine and norepinephrine levels showed a fourfold increase (р < 0.05). An injection of 0.5 mg of 6-OHDA caused a threefold increase of dopamine (р < 0.05) and a fivefold increase of norepinephrine (р < 0.01) concentration in comparison with the controls. On the 14th day, endotheline-1 level was 65 % higher than in the controls after a 0.25 mg 6-OHDA injection (р < 0.01) and 45 % higher after a 0,5 mg injection (р<0.05). At the same time, TNF-α levels increased by 43 % (р < 0.05) and 20 % (р < 0.05) respectively. We also revealed a dose-dependent change of IOP, a disturbance of pupillary light reaction and decreased ocular blood flow after an injection of neurotoxin. Conclusion. A single intravitreal injection of dopaminergic neurotoxin 6-OHDA in the amount of 0.25 or 0.5 mg per eye leads to a neuroinflammation and vascular disorders, which are the main pathogenetic pathways of neurodegeneration. To model its early phase, the 0.25 mg dose is preferable as it causes less dramatic functional disorders. The latter model can be useful for the investigation of retinal neurodegeneration pathogenesis, the search for early diagnostic and prognostic markers thereof and the estimation of therapy effectiveness.
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