YC-1玻璃体腔注射治疗猕猴视网膜中央静脉阻塞的实验研究

发布时间：2018-05-26 14:41

本文选题：视网膜中央静脉阻塞 + YC-1　；参考：《河北医科大学》2016年博士论文

【摘要】：视网膜中央静脉阻塞(central retinal vein occlusion,CRVO)是仅次于糖尿病视网膜病变的血管性疾病,患病率在0.7-1.6%之间,常常引起严重的视力下降甚至致盲。尽管确切的机制不清,但由于血管通透性增加导致的视网膜广泛出血及黄斑水肿(cystoids macular edema,CME)是主要的原因之一。目前,已有足够的证据表明VEGF在视网膜血管性疾病的发病过程中发挥着重要的作用。分子水平上,VEGF通过调节血管内皮细胞的增殖、移行以及增加血管内皮的通透性发挥病理作用。临床研究证明玻璃体腔注射抗VEGF药物,通过抑制VEGF与其受体相结合,从而抑制脉络膜,视网膜新生血管生长及血管渗漏,可以明显改善CRVO引起的黄斑水肿,不同程度改善患者视力。在包括老年性黄斑变性(AMD),视网膜静脉阻塞(RVO)及糖尿病视网膜病变(RD)的治疗中,抗VEGF药物的玻璃体腔注射治疗已成为一线的治疗方案。然而,随着抗VEGF药物的广泛应用,仍有诸多问题有待解决:由于药物半衰期短,需要频繁行眼内注药治疗以稳定视力,增加了发生眼内炎的潜在风险;部分难治性CRVO患者经治疗后,视力及黄斑水肿并没有改善甚至恶化,即所谓“反弹”效应;长期使用出现了色素上皮细胞及感光细胞层的萎缩现象。另一方面,炎症因子可能也发挥了一定的作用,临床研究证实:多种炎症因子如:IL1β,IL6,IL8,IL10,IL12,IL13,单核细胞趋化蛋白1(MCP-1),可溶性细胞黏附因子1(Si CAM-1),干扰素等在CRVO患者的玻璃体和房水中明显升高。通过玻璃体腔注射曲安奈德,有效抑制了VEGF和炎症因子的升高,减轻CRVO患者黄斑水肿,提高视力。然而,激素的严重副作用限制了它的广泛应用,研究表明经过曲安奈德玻璃体腔注射后,48-67%的患者出现不同程度的白内障,40%有眼内压升高的表现,0.1%的眼内炎风险。因此寻找新的靶向药物势在必行。在视网膜血管疾病的病理过程中,缺氧诱导因子1(HIF-1)起到了非常重要的作用,根据文献报道,包括VEGF,EPO在内的多种血管相关因子受到HIF-1二聚体的调控。YC-1作为HIF-1α的抑制剂,通过抑制HIF-1复合体的产生,在转录水平提前遏制VEGF等多种血管相关因子的产生,同时YC-1通过调控NF-KB通道(目前认为该通道是主要的炎症因子调控通道)间接抑制炎症因子的产生。因此YC-1兼具抗VEGF及抗炎的双重作用,极具研究价值。猕猴具有与人类类似的黄斑结构,通过激光建立CRVO猕猴动物模型后,经玻璃体腔注射YC-1,可以观察眼球组织结构,特别是黄斑结构的变化,以及玻璃体和视网膜中分子水平的变化,探讨YC-1玻璃体腔注射治疗CRVO疾病的可行性。第一部分YC-1药物在正常猕猴玻璃体腔中的药物动力学研究目的:在成年猕猴玻璃体腔中注射YC-1药物,观察其药物动力学变化,为进一步应用提供初步研究数据。方法:选取正常猕猴3只,共6只眼睛,应用YC-1;化学名称为3-(5-hydroxymethyl-2-furyl)-1-benzyl indazole(中文名称:3-(5-羟甲基-2-呋喃基)-1-苯甲基吲唑)(intel number.81560 5mg Cayman Chemical);溶解在DMSO(二甲基氩砜,浓度为0.01%)药物中,稀释成200μM浓度后,抽取90μl注入猕猴玻璃体腔中,并分别在注射后0.25小时,0.5小时,1小时,2小时,3小时,4小时,5小时,6小时,8小时,10小时,抽取玻璃体标本100μl,经样品预处理后,应用高效液相色谱技术+质谱联用法检测各时间点玻璃体中YC-1的浓度变化。并应用DAS 3.0药物动力学软件及PKSolver 2.0软件,计算YC-1的药物消除半衰期等药物动力学指标。结果:结果表明,猕猴眼玻璃体液的内源性物质对YC-1及内标的测定没有干扰,保留时间分别为1.25和1.80 min,表明该方法专属性良好。相关系数r均大于0.995,表明线性良好。药物动力学研究结果显示在给药后0.25小时,药物浓度为1.217μM,0.5小时为0.824μM,1小时为0.497μM,2小时为0.368μM,3小时为0.326μM,4小时为0.265μM,5小时为0.196μM 6小时为0.145μM,8小时为0.083μM。经软件分析YC-1药物半衰期为2.79小时。结论:通过液质联用方法测量玻璃体内YC-1药物动力学的变化,专属性和精密度良好,可以应用于YC-1在猕猴玻璃体腔中的药物动力学研究,结果符合预期的实验设计。本研究通过观察不同时间组YC-1在玻璃体内的质量浓度随时间变化的规律,发现玻璃体内YC-1质量浓度随时间的延长而迅速下降。YC-1在玻璃体内的消除半衰期t1/2为2.79小时。第二部分YC-1玻璃体腔注射对正常猕猴眼部组织的毒性研究目的:对YC-1玻璃体腔注射后其对眼部组织毒性问题进行研究,以期对该药在眼部应用的安全性进行评价。方法:共3只实验用成年猕猴共6只眼睛,其中每只猴子右眼作为实验组,行YC-1 90μl(浓度为200μM)玻璃体腔注射,左眼作为对照组,行二甲基氩砜90μl(DMSO,浓度为0.01%)玻璃体腔注射。观察时间点为术前和术后1天,1周,2周,1月。测量各实验眼眼压、裂隙灯观察结膜反应、前房炎症反应以及角膜透明性,眼底照相机观察眼底病变情况。相干光断层扫描(optic coherence tomography,OCT)观察黄斑区结构,眼底荧光血管造影检查血管病变情况。进行暗适应及明适应ERG检查。并在术后1月对摘除的眼球行光镜组织学检查。结果:YC-1玻璃体腔注射后各检查时间点,所有眼球角膜透明,无前房反应,也未见玻璃体积血、视网膜脱离等并发症。眼压,黄斑中心厚度无明显差异(P0.05)。眼底血管造影未见血管异常改变。ERG检查各组各时间点,实验组眼视杆细胞b波和视锥细胞a波和b波振幅与对照组眼相比差异无统计学意义(P0.05)。各时间点视网膜组织学检查未见异常改变。结论:应用YC-1(90μl浓度为200μM)注射于正常猕猴眼玻璃体内,无明显炎症反应,经过1月的随访观察,对视网膜结构和功能无显著性影响。第三部分猕猴视网膜中央静脉阻塞的模型的建立及视网膜功能及结构和玻璃体相关因子的测定目的:探讨多波长激光诱导猕猴视网膜中央静脉阻塞的可行性,观察视网膜结构和功能变化,为临床进一步认识该疾病的转归提供参考。方法:选择6只健康成年猕猴,首先行裂隙灯,眼底检查,OCT检查,眼底荧光血管造影,ERG检查及眼压检查,并确认无眼部疾患后,应用多波长激光的黄光封闭6只猕猴的右眼视盘周围所有主干静脉,制成CRVO模型,随后即刻行眼底荧光血管造影证实,并于术后6小时,1天,1周,2周,1月行相同检查。同时在造模前和造模后各时间点行玻璃体腔抽取玻璃体液200μl。分别行CBA及ELASA检测玻璃体细胞因子表达变化,包括:IL6,IL8,MCP-1及VEGF和HIF-1α。1个月后摘除眼球(每只猕猴摘除1眼,共3只左眼,3只右眼),进行视网膜的HE染色及VEGF,HIF-1α,Caspase3的免疫组化观察研究。结果:6只猕猴眼睛经激光制作的CRVO模型经FFA检查均成功,结果显示眼压在术后1天及1周有轻度升高,但无显著性差异(P0.05),虹膜面可见新生血管,黄斑水肿在1天,1周,2周有显著性升高(P0.05),并于1月恢复到术前水平(P0.05)。眼底可见广泛火焰出血,ERG显示视杆细胞b波和视锥细胞a波和b波显著下降(P0.05),眼底造影提示视网膜缺血渗漏明显,并可见无灌注区及新生血管,符合人视网膜中央静脉阻塞的基本变化。通过CBA及ELASA检测玻璃体炎症因子IL-6,IL-8及MCP-1表达水平在术后不同时间点出现了显著升高(IL-6和IL-8从术后1天,MCP-1从术后2周)(P0.05)。VEGF与HIF-1α表达也一致性升高,免疫组化研究发现,HIF-1α和VEGF在视网膜中表达明显升高,并伴有凋亡蛋白Caspase3的表达升高,光密度值均显示三种蛋白表达显著性升高(P0.05)。结论:激光制作的CRVO猕猴动物模型在术后出现了典型的黄斑水肿,视网膜出血及无灌注区等体征。视网膜电图显示视网膜功能不同程度受到破坏。测量玻璃体和视网膜中VEGF,HIF-1α表达显著升高,同时,玻璃体中炎症因子IL-6,IL-8,MCP-1表达上调。以上结果表明血管生长因子及炎症因子均参与了实验性CRVO的发病过程,激光所致猕猴CRVO可以模拟人类CRVO的发病过程,并为进一步药物干预治疗提供理想的动物模型。第四部分YC-1玻璃体腔注射治疗猕猴实验性视网膜中央静脉阻塞的研究目的:探讨YC-1玻璃体腔注射后对CRVO猕猴动物模型眼的视网膜结构,功能及视网膜和玻璃体内各种细胞因子的影响。方法:选用健康成年猕猴6只,每只猕猴右眼为YC-1实验组,行玻璃体腔注射YC-1,左眼为DMSO对照组,行DMSO玻璃体腔注射。行激光制作CRVO动物模型后,在术后1周,分别给予实验组和对照YC-1和DMSO玻璃体腔注射,分别在注射前和注射后1天,1周,2周、1月使用裂隙灯显微镜观察角膜、房水、晶状体、前节炎症反应情况;使用眼底照相,OCT及荧光眼底血管造影评估视网膜结构变化情况,并行眼压检查。同时采取玻璃体样本200μl,应用CBA及ELASA检测各时间点玻璃体样本中VEGF、HIF-1α、IL-6、IL-8、MCP-1等细胞因子的表达。并行ERG视网膜电图检查评估视网膜功能情况。随后在1个月时摘除眼球行HE染色及视网膜免疫组化研究。通过免疫组化方法检测视网膜中VEGF、HIF-1、Caspase3的表达。结果:YC-1实验组与DMSO对照组,经注射药物后,两组均可见虹膜面新生血管,视网膜出血,无灌注区及新生血管。各时间点,两组间眼压未见显著性差异(P0.05)。OCT检查可见黄斑区明显水肿,给予YC-1和DMSO注射后,发现在YC-1实验组,黄斑区水肿消退显著。在注射后1天,1周和2周均较DMSO对照组有显著性差异。ERG检查发现,给予YC-1玻璃体腔注射后1周视网膜电图的rod b波和cone a和b波均较DMSO组有显著改善。应用YC-1玻璃体腔注射后,IL-6、IL-8均得到明显的抑制,而MCP-1尽管有轻度降低,但与DMSO对照组比较没有显著性差异。此外,在应用YC-1后,玻璃体中HIF-1α和VEGF的表达显著降低,HE染色发现YC-1和DMSO二组的视网膜内核层和外核层细胞均较正常视网膜显著减少。免疫组化研究发现在YC-1治疗组,视网膜中HIF-1α,VEGF及Caspase3三种抗体的表达均显著受到抑制,应用图像分析系统测量了三种抗体在视网膜表达的光密度值,证实了三种蛋白表达均较DMSO组显著降低。结论:在造模后一周时,YC-1玻璃体腔注射后,可以显著改善黄斑水肿的程度,加快水肿吸收,改善ERG中视杆细胞b波和视锥细胞的a波和b波的波幅。同时抑制IL-6、IL-8、VEGF、HIF-1α在玻璃体内的表达,轻度抑制MCP-1的表达。在视网膜中降低VEGF和HIF-1α的表达,减少细胞凋亡,对视网膜细胞有保护作用。基于上述研究结果可以得出以下结论:1应用YC-1玻璃体腔注射对猕猴眼睛无明显毒性反应,对视网膜功能及结构无明显影响。2多波长激光制作猕猴CRVO动物模型,可实现模拟人眼CRVO的表现,其视网膜体征和功能均有一定相似性,可作为理想的实验模型,进行相关的药物研究。3应用YC-1玻璃体腔注射治疗激光诱导的猕猴CRVO动物模型,结果表明YC-1可以减轻黄斑水肿程度,改善视网膜功能,迅速抑制CRVO引起的玻璃体和视网膜中各种炎症因子及VEGF和HIF-1α的升高,降低视网膜细胞的凋亡程度,具有潜在的临床使用价值。
[Abstract]:Central retinal vein occlusion (CRVO) is a vascular disease second only to diabetic retinopathy. The prevalence rate is between 0.7-1.6% and often causes severe visual loss and even blindness. Although the exact mechanism is not clear, there is extensive retinal hemorrhage and macular edema caused by increased vascular permeability (Cys Toids macular edema, CME) is one of the main reasons. At present, there is sufficient evidence to show that VEGF plays an important role in the pathogenesis of retinal vascular diseases. At the molecular level, VEGF plays a pathological role by regulating the proliferation and migration of vascular endothelial cells and increasing the permeability of the intravascular skin. Anti VEGF drugs are injected into the cavity of the body. By inhibiting the combination of VEGF and its receptor, thus inhibiting the choroid membrane, the growth of retinal neovascularization and vascular leakage, it can obviously improve the macular edema caused by CRVO and improve the visual acuity of patients in varying degrees. It includes senile macular degeneration (AMD), retinal vein occlusion (RVO) and diabetic retinopathy (RD). In the treatment of the treatment, the vitreous intravitreal injection of anti VEGF drugs has become a first-line treatment. However, with the widespread use of anti VEGF drugs, there are still many problems to be solved: due to the short half-life of the drug, frequent intraocular injection is needed to stabilize the vision and increase the potential risk of endophthalmitis; some refractory CRVO patients After treatment, visual acuity and macular edema did not improve or even deteriorate, namely the so-called "rebound" effect; long term use of the atrophy of pigment epithelial cells and photoreceptor cells. On the other hand, the inflammatory factors may also play a role. Clinical studies have confirmed that a variety of inflammatory factors such as IL1 beta, IL6, IL8, IL10, IL12, IL13, mononuclear Cell chemoattractant protein 1 (MCP-1), soluble cell adhesion factor 1 (Si CAM-1), interferon in vitreous and aqueous humor of CRVO patients were significantly increased. The injection of Cu Ann Ned through the vitreous cavity effectively inhibited the increase of VEGF and inflammatory factors, alleviated macular edema and improved visual acuity in patients with CRVO. However, the severe side effects of the hormone restricted it. Widely used, studies have shown that after the injection of Cu Ann Ned's vitreous cavity, patients with 48-67% have different degrees of cataract, 40% with elevated intraocular pressure and 0.1% of the risk of endophthalmitis. Therefore, it is imperative to find new target drugs. In the pathological process of retinal vascular disease, hypoxia inducible factor 1 (HIF-1) is very important. As reported in the literature, a variety of vascular related factors, including VEGF, EPO, are regulated by the HIF-1 two polymer as an inhibitor of HIF-1 alpha. By inhibiting the production of the HIF-1 complex, the production of a variety of vascular related factors, such as VEGF, is inhibited in advance at the transcriptional level, and at the same time YC-1 is regulated by the NF-KB channel (currently believed to be the channel). The main inflammatory factor regulation channel indirectly inhibits the production of inflammatory factors. Therefore, YC-1 has both anti VEGF and anti-inflammatory effects and has great research value. Rhesus monkey has a macular structure similar to that of human. After establishing a CRVO macaque animal model by laser, the structure of eyeball tissue, especially macular knot, is observed by intravitreal injection of YC-1. The changes in the structure and the changes in the molecular level in the vitreous and retina, the feasibility of YC-1 intravitreal injection for the treatment of CRVO disease is discussed. Part 1 the pharmacokinetics of YC-1 in the normal rhesus monkey's vitreous cavity is studied in order to observe the pharmacokinetics of YC-1 in the adult rhesus monkey's glass cavity. Methods: a total of 3 normal macaques and 6 eyes were selected to use YC-1. The chemical name was 3- (5-hydroxymethyl-2-furyl) -1-benzyl indazole (Chinese Name: 3- (5- hydroxymethyl -2- furanyl) -1- benzyl indazole) (Intel number.81560 5mg), and dissolved in the drug (two methyl argon sulfoxide, 0.01%), After diluted to 200 M concentration, 90 Mu l was injected into the glass cavity of macaque, and 0.25 hours, 0.5 hours, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 6 hours, 6 hours, 8 hours, 10 hours, respectively, were extracted from the vitreous body of the rhesus macaque, respectively. After sample pretreatment, high performance liquid chromatography and mass spectrometry were used to detect YC in the vitreous body of each time point. The concentration changes of -1. And using the DAS 3 pharmacokinetic software and the PKSolver 2 software to calculate the pharmacokinetic indexes of the drug elimination half life of YC-1. Results: the results showed that the endogenous substances of the macaque eye glass body fluid were not interfered with the determination of YC-1 and the internal standard, and the retention time was 1.25 and 1.80 min respectively, indicating that the method was exclusive and good. The correlation coefficient r was more than 0.995, indicating a good linearity. The pharmacokinetic study showed that the drug concentration was 1.217 mu M, 0.5 hours was 0.824 mu M, 1 hours 0.497 mu M, 2 hours 0.368 u M, 3 hours 0.326 M, 4 hour 0.265 M, 2 hour M hour M.. The half-life of YC-1 was 2.79 hours. Conclusion: the changes in the pharmacokinetics of YC-1 in the vitreous body were measured by the method of liquid mass spectrometry, and the specificity and precision were good. It could be applied to the pharmacokinetics study of YC-1 in the macaque glass cavity. The results accorded with the expected experimental design. This study was conducted by observing different time groups of YC-1 in the glass body. It was found that the mass concentration of YC-1 in the vitreous body rapidly decreased with time and reduced the half-life of.YC-1 in the glass body for 2.79 hours. The toxicity of the second part of the YC-1 glass cavity injection on the eye tissues of normal rhesus monkeys: the toxicity to the ocular tissue after the injection of YC-1 vitreous cavity. The problem was studied in order to evaluate the safety of the drug in the eye application. Methods: a total of 6 eyes were used in 3 adult rhesus monkeys, of which the right eye of each monkey was taken as the experimental group. The YC-1 90 Mu L (concentration 200 M) was injected into the glass cavity, the left eye was used as the control group, and the two methyl argon sulfoxide 90 L (DMSO, 0.01%) was injected into the glass body cavity. The observation time was 1 days before and 1 days, 1 weeks, 2 weeks, January. The intraocular pressure of the experimental eyes was measured, the conjunctiva reaction was observed in the slit lamp, the inflammation of the anterior chamber and the corneal transparency, the ocular fundus camera observed the lesion of the fundus. The optic coherence tomography (OCT) was used to observe the macular region, and the fundus fluorescein angiography was used to examine the blood vessels. Pathological changes. Dark adaptation and adaptive ERG examination. And the ocular microscopy examination of the exucleation of the eyeball in January. Results: every examination time after the injection of YC-1 glass body cavity, all cornea of the eyeball was transparent, no anterior chamber reaction, no vitreous blood, retinal detachment and other complications. There was no significant difference in intraocular pressure and macular center thickness (P0.0 5). No abnormal changes of blood vessels in the ocular fundus angiography were found in each time point of.ERG examination. There was no significant difference in the B and b wave amplitudes of the eye rod cells in the experimental group compared with the control group (P0.05). There was no abnormal change in the retinal histological examination at all time points. Conclusion: the application of YC-1 (the concentration of 90 Mu l to 200 mu M) was injected into the normal Actinidia. There is no obvious inflammatory response in the monkey eye glass. After the follow-up observation in January, there is no significant effect on the structure and function of the retina. The establishment of the model of central retinal vein occlusion in third macaques and the determination of retinal function and structure and the related factors of vitreous body: To explore the central vein of rhesus macaque induced by multi wavelength laser The feasibility of blocking, observing the changes of retinal structure and function, provides reference for further understanding of the prognosis of the disease. Methods: 6 healthy adult macaques were selected, first of which were slit lamp, fundus examination, OCT examination, fundus fluorescein angiography, ERG examination and intraocular pressure examination, and the application of multi wavelength laser yellow light after no ocular disease was confirmed. All the main veins around the right eye disc around 6 rhesus monkeys were closed, and the CRVO model was made. Then the fundus fluorescein angiography was performed immediately, and the same examination was performed at 6 hours, 1 days, 1 weeks and 2 weeks after the operation. At the same time, the vitreous body fluid was extracted by the vitreous body fluid 200 mu before and after the modeling, and the vitreous cells were detected by CBA and ELASA respectively. Factor expression changes, including: IL6, IL8, MCP-1 and VEGF and HIF-1 alpha.1 months after the removal of the eyeball (1 eyes from each rhesus monkey, 3 left eyes, 3 right eyes), HE staining of the retina and immunohistochemical observation of VEGF, HIF-1 alpha and Caspase3. Results: 6 monkeys' eyes were successfully made by laser for FFA, and the results showed intraocular pressure. There was a slight increase in the 1 and 1 weeks after operation, but there was no significant difference (P0.05). The neovascularization was seen on the iris surface. The macular edema had a significant rise in 1 days, 1 weeks and 2 weeks (P0.05), and was restored to the preoperative level (P0.05) in January. Extensive flame hemorrhage was found in the fundus, and ERG showed a significant decrease in the A and B waves (P0.05) of the B and conical cells of the optic cells (P0.05). The findings suggest that the retinal ischemic leakage is obvious, and the non perfusion area and neovascularization can be seen in accordance with the basic changes in the central retinal vein occlusion. The levels of vitreous inflammatory factors IL-6, IL-8 and MCP-1 are significantly increased by CBA and ELASA (IL-6 and IL-8 from 1 days after operation, MCP-1 from 2 weeks after operation) (P0.05).VE (P0.05).VE The expression of GF and HIF-1 alpha was also elevated. The immunohistochemical study found that the expression of HIF-1 alpha and VEGF increased significantly in the retina, accompanied by the increase of the expression of apoptotic protein Caspase3, and the value of light density showed a significant increase in the expression of three proteins (P0.05). Conclusion: the laser made CRVO macaque animal model appeared typical Huang Banshui after the operation. Swelling, retinal hemorrhage and instillation areas. Electroretinogram showed that retinal function was damaged in varying degrees. The expression of VEGF, HIF-1 a in the vitreous and retina was significantly increased, and the expression of inflammatory factors IL-6, IL-8, and MCP-1 in the vitreous body was up-regulated. The above results showed that both vascular growth factor and inflammatory factor were involved in experimental CR. The pathogenesis of VO, laser induced macaque CRVO can simulate the pathogenesis of human CRVO, and provide an ideal animal model for further drug intervention. Fourth part YC-1 vitreous intravitre injection for experimental retinal vein occlusion in rhesus monkeys: To explore the model eye of CRVO rhesus monkeys after YC-1 vitreous injection. Methods: the effects of retinal structure, function and various cytokines in the retina and vitreous body. Methods: 6 healthy adult macaques were selected, the right eye of each macaque was YC-1 experimental group, YC-1 was injected into the vitreous cavity, the left eye was DMSO control group, and DMSO glass cavity was injected. After the laser production of CRVO animal model, the experimental group was given 1 weeks after the operation, and the experimental group and the pair were given respectively. YC-1 and DMSO vitreous intravitre were injected before and 1 days, 1 weeks and 2 weeks after injection. In January, corneal, aqueous humor, lens, and anterior inflammatory reaction were observed by slit light microscope, retinal structure changes were evaluated by fundus photography, OCT and fluorescein angiography, and intraocular pressure was checked in parallel with 200 l of vitreous samples. CBA and ELASA were used to detect the expression of VEGF, HIF-1 alpha, IL-6, IL-8, MCP-1 in the vitreous samples of each time point. The retinal function was evaluated by parallel ERG electroretinogram. Then the eyeball was extirpated with HE staining and retina immunohistochemical study at 1 months. VEGF, HIF-1, Caspase3 in retina were detected by immunization. Results: YC-1 experimental group and DMSO control group, after the injection of drugs, two groups of iris neovascularization, retinal hemorrhage, no perfusion area and neovascularization. At all time points, there was no significant difference in intraocular pressure between the two groups (P0.05).OCT examination showed obvious edema in the macular area. After the injection of YC-1 and DMSO, it was found in the YC-1 experimental group, macula 1 days after injection, 1 and 2 weeks after injection, there was significant difference between the.ERG and the DMSO control group. The rod b wave and cone a and b wave of the electroretinogram after the injection of YC-1 glass body cavity were significantly better than those in the DMSO group. But there was no significant difference compared with the DMSO control group. In addition, after the application of YC-1, the expression of HIF-1 alpha and VEGF in vitreous decreased significantly, HE staining.
【学位授予单位】：河北医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R774.1

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