脑源性神经营养因子与视神经和视网膜

脑源性神经营养因子是近来研究较多的一种神经营养因子。本文就其在视神经和视网膜方面的基础研究作一综述。     

白血病抑制因子(LIF)对视网膜视锥细胞氧化损伤的保护作用及机制

目的 研究氧化损伤条件下,白血病抑制因子(leukemia inhibitory factor,LIF)对视网膜视锥细胞活性的影响及其作用机制.方法 体外培养小鼠视网膜光感受器视锥细胞(661 W细胞株),根据干预药物不同,随机分为正常对照组、LIF干预组、H2O2干预组、S3I201干预组、H2O2+LIF干预组、H2O2+S3I201干预组、H2O2 +LIF+ S3I201干预组.采用MTT比色法和Western blot法检测LIF预处理对氧化损伤后视锥细胞活性及其相关信号转导通路因子STAT3蛋白表达及其磷酸化水平的影响.运用S3I201阻断STAT3信号通路后,采用MTT比色法和实时荧光定量PCR检测STAT3信号通路阻断对氧化损伤后视锥细胞活性以及抗凋亡因子bcl-2和bcl-xl mRNA的表达影响.结果 与H2O2干预组相比,H2O2+ LIF干预组p-Tyr705-STAT3蛋白的相对表达量明显增加,H2O2+ S3I201干预组p-Tyr705-STAT3蛋白的相对表达量显著下降,差异均有统计学意义(均为P＜0.05).与H2O2干预组相比,H2O2+ LIF干预组661 W细胞的细胞活性显著提高,差异有统计学意义(P＜0.05);与H2O2+ LIF干预组相比,H2O2+ LIF+S3I201干预组661 W细胞的细胞活性显著下降,差异有统计学意义(P＜0.05).与正常对照组相比,LIF干预组、H2O2干预组和H2O2+LIF干预组bcl-2 mR-NA和bcl-xl mRNA的相对表达量均显著增加,差异均有统计学意义(均为P＜0.05);与H2O2+LIF干预组相比,H2O2+LIF+S3I201干预组bcl-2 mRNA和bcl-xl mRNA的相对表达量均显著下降(均为P＜0.05).结论 LIF对视锥细胞氧化损伤具有保护作用,其可能通过激活STAT3信号通道刺激抑制凋亡因子bcl-2和bcl-xl的表达增加而发挥作用.     

退行性视网膜病变中睫状神经营养因子神经保护作用的研究进展

多项体内外及临床试验结果均证实睫状神经营养因子(CNTF)对光感受器细胞具有良好的神经保护作用,同时也对视网膜多种神经细胞的结构和功能产生不同的影响.CNTF对光感受器细胞保护作用的分子机制涉及Stat、Erk及Akt等信号传导途径,其中Müller细胞发挥着重要作用.细胞包囊技术为CNTF提供了有效的给药途径,在多种退行性视网膜病变的动物模型中均取得良好疗效,其临床应用中的安全性和有效性正在进行评估,这将为CNTF进入临床应用奠定基础.(中华眼科杂志,2011,47:568-572)

Abstract：

Ciliary neurotrophic factor (CNTF) has been showing neuroprotective effects on photoreceptors in a variety of in vivo and in vitro experiments and clinical trials. CNTF causes morphological and functional alterations in various retinal nerve cells. The neuroprotection mechanism of CNTF involves STAT-dependant, ERK-dependant, and Akt-dependant signaling technology (ECT) device is an efficient administration approach to deliver CNTF into the eyes, which is effective in retarding photoreceptor degeneration in several animal models with retinal degenerative diseases. The safety and efficiency of the device in clinical trials are also being evaluated currently for further clinical use in human eyes as a potential treatment.     

炎症因子在圆锥角膜发病机制中的研究进展

圆锥角膜(keratoconus,KC)是一种渐进性角膜变薄性疾病,通过角膜膨隆,导致锥状外观,瘢痕形成以及视力下降。各种遗传因素、环境因素(眼摩擦,隐形眼镜磨损,紫外线照射)都与其病因相关。除了遗传和环境因素外,在此过程中炎性发病机制也越来越受到学者重视。本文涵盖了与之最相关和最近发表的关于炎症生物标志物,以进一步阐述圆锥角膜的发病机制,以期为圆锥角膜的治疗提供新思路。     

SIRT1在糖尿病视网膜病变发病机制中的作用

沉默信息调节因子1（silent information regulator1,SIRT1）属于第Ⅲll型组蛋白去乙酰化酶,与糖尿病视网膜病变发病相关.SIRT1可通过抑制炎性反应,抑制氧化应激对视网膜细胞的损害,影响血管内皮生长因子的生成,抑制视网膜细胞凋亡,从而影响糖尿病视网膜病变的发病及进展.目前已有数个白藜芦醇（SIRT1激动剂）制剂进入治疗2型糖尿病的临床试验阶段,其治疗效果还需进一步验证.     

HIV相关视网膜神经病变发病机制及临床特点的研究进展

人类免疫缺陷病毒(human immunodeficiency virus, HIV)感染患者眼部病变因其对患者生存质量的影响日益引起学者关注。随着HIV治疗方法的不断改善,眼部机会性感染疾病减少,而HIV相关视网膜神经病变越来越受到学者关注。研究发现HIV相关视网膜神经病变包括神经纤维层变薄,血管改变等一系列视网膜视神经结构改变,导致患者视敏感度下降、视野缺损、色觉障碍等。而HIV相关视网膜视神经病变发病机制尚未完全明确,研究发现可能与HIV病毒直接破坏视网膜视神经组织,慢性炎症,血-视网膜屏障破坏等相关。了解HIV相关视网膜视神经病变的病变特点及可能的机制,有望为疾病的治疗提供新思路与途径,提高HIV感染患者的生存质量。     

糖尿病视网膜病变微血管神经病变发病机制的研究进展

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病(diabetic melitus,DM)常见且严重的微血管并发症之一。在国外,DR是工作人群(20～64岁)首位的致盲因素; 在国内,DR的发病率和致盲率也在逐年增加,严重影响患者的生存质量。以往对DR发病机制和治疗的研究主要集中在微血管方面,近年来,随着研究的深入,越来越多的学者认为DR不再单纯是一种微血管病变,同时伴随着视网膜神经退行性改变,但国内外文献对DR的微血管病变与神经退行性改变发病机制的研究多是单一的。本文就DR微血管病变与神经退行性改变之间的关系做一综述。     

神经营养因子与生长因子在体外对人视网膜神经节细胞之作用

目的 研究神经营养因子(neurotrophic factor)与生长因子(growth factor)在体外对人视网膜神经节细胞(retinal ganglion cell,RGC)生存的作用。 方法 从捐献的尸体眼球分离并培养RGC。RGC之鉴定系根据形态学与免疫细胞化学研究。将各种神经营养因子与生长因子分别加入培养液。对RGC计数,并与未加任何因子的对照组相比较。 结果 未加任何因子的培养中不见或仅有极少量的RGC。加有神经营养蛋白-3(neurotrophin-3,NT-3)、神经生长因子(nerve growth factor,NGF)、表皮生长因子(epidermal growth factor,EGF)与血小板源性生长因子(plate derived growth factor, PDGF)的培养亦同。加有下列因子的培养中有较多的RGC出现,计数为(细胞数/每10个显微镜野)：脑源性神经营养因子(brain derived neurotrophic factor,BDNF)：4.08;睫状神经营养因子(ciliary neurotrophic factor,CNTF)：1.23;神经营养蛋白-4/5(neurotrophin-4/5,NT-4/5)：2.63;碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)：2.65。 结论 BDNF、NT-4/5、bFGF与CNTF在体外能改善人RGC之生存,而NGF、NT-3、EGF与PDＧF则不能。 (中华眼底病杂志, 1999, 15: 149-152)     

高水平稳定表达人睫状神经营养因子细胞株的建立

目的 建立能稳定且高水平表达人睫状神经营养因子（CNTF）的永久细胞株。方法 采有阳离子脂质体介导CNTF表达质粒转染C2C12、NIH3T3、、CRL-2302细胞，经氨甲喋呤筛选出抗性克隆后，分别采用原位杂交检测细胞中CNTF mRNA的表达，采用免疫组织化学染色、Western blot方法检测细胞浆中CNTF蛋白质的表达，采用ELISA法检测培养液中CNTF的分泌水平。结果 不同的克隆产生和分泌CNTF的能力不同，但其中产生和分泌CNTF能力最强的克隆其培养液中CNTF的质量浓度分别是C2C12-CNTF 11400pg/ml、NIH3T3-CNTF9069.071pg/ml、HLF-CNTF91046.15pg/ml及CRL-2302-CNTF77578.4pg/ml。结论 构建的多株细胞株均能持续、稳定、高水平表达和分泌CNTF。     

细胞因子信号抑制因子在眼科的研究进展

细胞因子信号抑制因子(SOCS)是大多数细胞因子信号转导通路的负性调节因子, SOCS不仅与全身免疫性疾病的发生有关,而且在眼科疾病如葡萄膜炎的发生、角膜损伤后的愈合、白内障的发生和沙眼衣原体感染的机制等方面起着重要作用。本文主要就SOCS的分子结构、功能及其在眼科的研究进展作一综述。     

Exogenous leukemia inhibitory factor (LIF) attenuates retinal vascularization reducing cell proliferation not apoptosis

To study the effect of leukemia inhibitory factor (LIF) on rat retinal vascular development, Sprague-Dawley rats at postnatal age 3 days (p3) were given intraperitoneal (IP) LIF and analysis performed at p6 (p3/6). p7 rats were given intravitreous (IV) LIF and analysis performed at p9 (p7/9). Control animals were PBS injected. At the time of analysis retinal flatmounts were prepared and stained with Griffonia lectin and activated caspase-3. The retinal peripheral avascular area was measured and number of apoptotic cells counted. In vitro, human retinal microvascular endothelial cells (RMVECs) were cultured in media containing LIF, with and without neutralizing antibody to LIF. Cells were stained with activated caspase-3 and apoptotic cells counted. Proliferation was measured by counting cell numbers, and cell cycle stage was determined using propidium iodide staining and FACS analysis. LIF injected either IP or IV had no effect on body weight or total retina area, but significantly increased the peripheral retinal avascular area. In both IP and IV injected groups there was no difference in the number of apoptotic cells between PBS- or LIF-injected groups; although in the p7/9 retinas, both injected groups had significantly more apoptotic cells than the non-injected group. In vitro, there was no effect of LIF on RMVEC apoptosis; however, cell counts were significantly lower in the LIF-treated group. Antibody to LIF restored the cell counts to untreated levels. LIF reduced the number of cells in S phase. LIF attenuates retinal vascular development in vivo through growth arrest, and not apoptosis, of endothelial cells.     

Cannabinoids and the eye

Cannabis ranks among the most commonly used psychotropic drugs worldwide. In the context of the global movement toward more widespread legalisation, there is a growing need toward developing a better understanding of the physiological and pathological effects. We provide an overview of the current evidence on the effects of cannabinoids on the eye. Of the identified cannabinoids, Δ⁹-tetrahydrocannabinol is recognized to be the primary psychotropic compound, and cannabidiol is the predominant nonpsychoactive ingredient. Despite demonstrating ocular hypotensive and neuroprotective activity, the use of cannabinoids as a treatment for glaucoma is limited by a large number of potential systemic and ophthalmic side effects. Anterior segment effects of cannabinoids are complex, with preliminary evidence showing decreased corneal endothelial density in chronic cannabinoid users. Experiments in rodents, however, have shown potential promise for the treatment of ocular surface injury via antinociceptive and antiinflammatory effects. Electroretinography studies demonstrating adverse effects on photoreceptor, bipolar, and ganglion cell function suggest links between cannabis and neuroretinal dysfunction. Neuro-ophthalmic associations include ocular motility deficits and decrements in smooth pursuit and saccadic eye movements, although potential therapeutic effects for congenital and acquired nystagmus have been observed.     

神经生长因子及其受体与视神经视网膜疾病的研究进展

目前关于神经生长因子在视网膜视神经疾病中的作用研究很多 ,但观点很不一致。本文着重论述神经生长因子及其受体在视觉系统的分布、视神经损伤、缺血性视网膜疾病、视网膜变性疾病及增生性玻璃体视网膜疾病中的作用。     

神经营养素在视网膜及视神经疾病方面的研究

神经营养素是一类结构和功能相近的多肽类家族,广泛分布于人体各种组织细胞中,有着重要的生物学特性,在临床已广泛应用,在眼科方面也有研究。对神经营养素及其受体在视网膜组织的分布作了描述和分析,并对神经营养素在视网膜及神经疾病方面的基础及临床研究作了综述。     

视神经损伤时视网膜睫状神经营养因子受体的表达

目的研究睫状神经营养因子受体于视神经损伤后不同时间在视网膜中的表达情况,探讨外源性的睫状神经营养因子在神经损伤疾病中的应用价值。方法采用钳夹视神经的方法建立神经损伤的模型,在损伤后1、7、14、28d获取视网膜,提取总RNA及总蛋白,用半定量逆转录聚合酶链反应(RT-PCR)测定视网膜中睫状神经营养因子受体(CNTFR)αmRNA的表达,用WesternBlot方法了解损伤后不同时间CNTFRα蛋白水平的表达。结果在正常大鼠视网膜内CNTFRαmRNA无表达,在损伤后的1、7、14、28d均有一定水平的CNTFRαmRNA的表达,与正常对照比较差别具有显著性意义(P<0.01);损伤后备时间均有CNTFRα蛋白的表达,但CNTFRα蛋白的表达较弱。结论神经损伤后CNTF的表达先短暂升高以后持续下调,而CNTFRα-mRNA在损伤后4周内均有一定量的表达,提示补充外源性CNTF可能改善神经再生的微环境而发挥保护效应。     

姜黄素对糖尿病大鼠视网膜中巨噬细胞游走抑制因子表达的影响

目的检测巨噬细胞游走抑制因子（MIF）在糖尿病大鼠视网膜中的表达,探讨MIF在糖尿病视网膜病变（DR）中的作用及姜黄素早期干预对其表达的影响。方法对30只清洁级SD大鼠行腹腔注射质量分数1%链脲佐菌素（STZ）诱导建立糖尿病动物模型,选取其中的20只随机分为糖尿病组和姜黄素治疗组,各10只,另取10只正常匹配的大鼠作为正常对照组。姜黄素治疗组自STZ注射后3d起给予含羧甲基纤维素的姜黄素200mg/（kg.d）灌胃,共8周,正常对照组和糖尿病组给予等量的羧甲基纤维素灌胃。动物处死后收集各组大鼠眼球,苏木精-伊红染色观察大鼠视网膜组织的病理变化;采用ELISA法检测各组大鼠视网膜组织中MIF的表达;应用免疫组织化学法观察各实验组大鼠视网膜中MIF的表达及定位;透射电镜下观察大鼠视网膜超微结构的改变。结果与正常对照组比较,糖尿病组大鼠和姜黄素治疗组大鼠血糖明显升高,差异均有统计学意义（P〈0.01）;姜黄素治疗组大鼠血糖水平明显低于糖尿病组,差异有统计学意义（P〈0.01）。与正常对照组比较,糖尿病组和姜黄素治疗组大鼠体重明显下降,差异均有统计学意义（P〈0.01）;姜黄素治疗组大鼠体重明显大于糖尿病组,差异有统计学意义（P〈0.01）。糖尿病组大鼠视网膜变薄,但姜黄素治疗组大鼠视网膜接近正常。免疫组织化学检测表明,糖尿病组视网膜组织中含有大量MIF阳性细胞,姜黄素治疗组视网膜中MIF表达明显少于糖尿病组（P〈0.01）。ELISA法检测结果显示,糖尿病组MIF的表达较正常对照组显著升高（P〈0.01）;姜黄素治疗组MIF的表达较糖尿病组明显下降（P〈0.01）。透射电镜下糖尿病组大鼠视网膜光感受器内外节水肿,毛细血管内皮细胞和周细胞染色体边集;姜黄素治疗组大鼠视网膜超微结构的改变轻微。结论 DR与视网膜的炎性改变有关,视网膜组织中MIF的高表达参与早期DR的发生发展。姜黄素可下调MIF的表达,其早期干预可延缓DR的发病进程。     

Ocular and orbital involvement in leukemia

Leukemia may involve almost any ocular tissue, by direct infiltration, by hemorrhage, and by ischemic changes. Both acute and chronic leukemia can cause ocular signs, either initially or later in the disease process; the clinical features and pathologic correlations of this involvement are reviewed. Also, various chemotherapeutic agents used to treat leukemia may cause ocular toxicity. Recently, bone marrow transplants have been performed more frequently in an attempt to prolong patient survival; if graft-versus-host disease results, one symptom is dry eyes from alacrima. Superimposed infection due to immunosuppression can occur from the disease itself or from treatment. Recognition by the ophthalmologist of the various ocular signs is important in assessing the course and prognosis of leukemia.     

复方樟柳碱联合神经生长因子治疗视神经视网膜挫伤26例

目的:观察复方樟柳碱联合神经生长因子(NGF)治疗视神经视网膜挫伤的疗效。方法:视神经视网膜挫伤患者26例31眼,应用复方樟柳碱联合神经生长因子(NGF)治疗,此为治疗组。并以用血管扩张剂、胞二磷胆碱、维生素治疗22例28眼为对照组。结果:两组疗效(主要观察指标是视力)比较显示,治疗组疗效(94%)明显优于对照组(64%),差异具有显著性(P<0.05)。结论:复方樟柳碱联合神经生长因子治疗视神经视网膜挫伤有显著疗效。     

Phosphodiesterase inhibitors and the eye

Phosphodiesterase type 5 (PDE5) inhibitors are effective oral treatments for erectile dysfunction and have become one of the most widely prescribed medications worldwide. The mechanism of action is to reduce the degradation of cyclic GMP (cGMP) potentiating the effect of nitric oxide in the corpus cavernosum and allowing erectile function to occur by consequent relaxation of penile smooth muscle. Because of the presence of PDE5 in choroidal and retinal vessels these medications increase choroidal blood flow and cause vasodilation of the retinal vasculature. The most common symptoms are a blue tinge to vision and an increased sensitivity to light. There have been reports of non-arteritic anterior ischaemic optic neuropathy and serous macular detachment in users of PDE5 inhibitors, although a causal relationship has not been conclusively shown. Despite the role of cGMP in the production and drainage of aqueous humour these medications do not appear to alter intraocular pressure and are safe in patients with glaucoma. All PDE5 inhibitors weakly inhibit PDE6 located in rod and cone photoreceptors resulting in mild and transient visual symptoms that correlate with plasma concentrations. Psychophysical tests reveal no effect on visual acuity, visual fields or contrast sensitivity; however, some studies show a mild and reversible impairment of blue-green colour discrimination. PDE5 inhibitors transiently alter retinal function on electroretinogram testing but do not appear to be retinotoxic. Despite the role of cyclic nucleotides in tear production there is no detrimental effect on tear film quality. Based on the available evidence PDE5 inhibitors have a good ocular safety profile.