神经营养因子治疗视网膜色素变性的研究进展

神经营养因子是能够促进神经元存活、生长、分化及维持其功能的多效性肽类因子的总称,可被作为有效的神经保护剂用于治疗多种神经变性类疾病.视网膜色素变性(RP)是以光感受器-视网膜色素上皮复合体损害为主的高度遗传异质性视网膜变性疾病,神经营养因子作为不针对致病基因的RP治疗策略,其疗效已在多种视网膜变性的动物模型中得到证实.以病毒为载体的转基因治疗和细胞包囊技术为神经营养因子提供了有效的给药途径,可使疗效明显提高.对神经营养因子在视网膜中的表达及其调节、受体分布特点、作用通路、疗效及副作用等方面的深入研究为神经营养因子的临床应用奠定了基础.     

睫状神经营养因子对视网膜色素变性中感光细胞的作用

遗传性视网膜色素变性类疾病是人类的主要致盲眼病之一,目前尚无有效阻止病变进展和恢复视网膜功能的治疗方法.此类疾病的最后结果是感光细胞不可逆的凋亡.阻断感光细胞走向凋亡的进程是近年来研究的热点.在大量的体内外实验中发现,很多神经生长因子对遗传性视网膜色素变性类疾病有一定的治疗作用,其中睫状神经营养因子保护感光细胞、延缓感光细胞凋亡的作用颇受关注.本文就近年来睫状神经营养因子对视网膜色素变性疾病中感光细胞的作用研究作一综述.     

视网膜色素变性治疗研究进展

视网膜色素变性(retinitis pigmentosa,RP)是一组遗传性视网膜疾病,其特征是渐进性感光细胞和视网膜色素上皮(RPE)细胞功能障碍,是世界范围内常见的致盲性眼病,且缺乏有效的治疗方法。目前RP的治疗方法包括干细胞治疗、基因治疗、神经保护治疗、营养疗法、高压氧疗法、视网膜移植和中医治疗。本文综述了近年来国内外有关RP治疗的研究进展。     

脑源性神经营养因子治疗视网膜色素变性的研究进展

脑源性神经营养因子(BDNF)是一种由脑组织合成并广泛分布于中枢神经系统的小分子碱性蛋白.研究发现,BDNF对视网膜神经节细胞(RGCs)、视网膜感光细胞(RPCs)和视网膜色素上皮(RPE)细胞均有保护、营养及抗凋亡作用.视网膜色素变性(RP)是由于RPCs及RPE细胞凋亡引起的视网膜退行性疾病.RP动物模型证实了BDNF的长期给药对于RP的治疗价值.然而BDNF在体内的半衰期较短,且无法跨越血-视网膜屏障由循环系统输送到视网膜,这给BDNF用于RP的治疗带来了挑战.为了使BDNF在眼内可以稳定持续地释放,多种新型给药方式已被尝试,包括基因工程技术、细胞移植技术、高分子材料缓释系统及滴眼液等.本文就BDNF对RP治疗的研究现状及BDNF的新型给药方式做一综述.     

视网膜色素变性的治疗进展

视网膜色素变性（RP）是一种以视杆细胞和视锥细胞营养不良为特征的遗传性致盲性眼病。临床特点为夜盲,视野缩小,视网膜上出现骨细胞样色素沉着。发病率较高,预后差。RP是单基因遗传病,病因主要与基因变突、视网膜色素上皮吞噬功能及免疫功能异常有关。到目前为止RP缺乏有效的治疗手段,仍被WHO划归为不可治疗盲,治疗仅限于延缓变性过程,但国内外就该病的基因治疗、视网膜移植、人工恢复视觉、神经保护、抗凋亡治疗、药物治疗、营养治疗等方面已取得了一定的进展,本文现综述如下。     

神经营养因子治疗视网膜色素变性的研究进展

目前为止发现了30余种视网膜色素变性（RP）的致病相关基因,发病机制研究提示凋亡可能是它们引起光感受器细胞萎缩的共同病理途径.神经营养因子是一类对神经系统的分化、发育,对神经元的存活,轴突再生均有重要作用的细胞因子.它们可能通过调控视网膜光感受器细胞的凋亡过程起到神经保护作用,有望成为治疗RP的有效药物.本文对近年来神经营养因子的光感受器保护作用、给药途径、治疗机制、副作用等方面的研究状况进行综述,其中基因工程改造的神经营养因子和基因修饰细胞半透膜埋植系统的研究取得了进展.     

脑源性神经营养因子对视网膜神经血管单元的保护作用

神经血管耦合以神经血管单元(NVU)为基础，发挥神经细胞与微血管之间信号传导、代谢调节等功能并共同组成屏障结构维持微环境稳态。神经血管单元在视网膜中广泛分布，与视网膜正常生理功能的维持关系密切，而各种原因引起的视网膜神经血管稳态失衡会导致多种视网膜疾病，如糖尿病视网膜病变(DR)、青光眼、视网膜色素变性(RP)及年龄相关性黄斑变性(ARMD)等。脑源性神经营养因子(BDNF)在视网膜也有广泛分布，通过与其受体TrkB结合发挥促神经生长和损伤修复等功能。近年来，研究发现BDNF在视网膜神经血管单元稳态失衡早期，即神经退行阶段可发挥损伤保护作用，同时减少神经来源的促血管生成物质，延缓疾病进程并为早期干预和治疗提供了新策略新思路。     

用科学的态度正确认识视网膜色素变性

视网膜色素变性(RP)是最常见的遗传性致盲眼底病,具有高散发性和高临床异质性.除了常见的遗传类型外,还具有双基因遗传,线粒体遗传,不完全显性遗传等新遗传方式.RP的表型复杂,Peripherin/RDS、RHO、RP2和RP3等RP基因出现了基因型和表型不一致现象,中心性、单发性、无色素性和缓慢型视网膜变性等少见RP具有复杂的临床表型.视网膜移植术、视网膜植入术、药物及神经营养因子治疗和基因治疗等治疗体系已经建立.但是,一些眼科医师对于RP治疗的新进展和新知识了解不多,因此积极地更新知识,以科学的态度正确地认识RP非常必要.(中华眼科杂志,2009,45:193-195)     

神经营养因子治疗视网膜色素变性的研究进展

目前为止发现了30余种视网膜色素变性(RP)的致病相关基因,发病机制研究提示凋亡可能是它们引起光感受器细胞萎缩的共同病理途径。神经营养因子是一类对神经系统的分化、发育,对神经元的存活,轴突再生均有重要作用的细胞因子。它们可能通过调控视网膜光感受器细胞的凋亡过程起到神经保护作用,有望成为治疗RP的有效药物。本文对近年来神经营养因子的光感受器保护作用、给药途径、治疗机制、副作用等方面的研究状况进行综述,其中基因工程改造的神经营养因子和基因修饰细胞半透膜埋植系统的研究取得了进展。     

细胞因子对视网膜变性疾病防治作用的研究进展

视网膜变性疾病是严重的致盲性眼病,感光细胞的凋亡是其主要表现。细胞因子是机体组织细胞合成和分泌的小分子多肽类因子,参与多种细胞生理功能的调节,减少细胞的凋亡。随着对各种细胞因子,特别是神经营养因子作用机理的不断阐明,越来越多的研究发现外源性的给予或内源性的诱发其表达,对于变性视网膜光感受器的保护是有积极作用的。本文将近年来用于视网膜变性疾病方面研究的神经营养因子和部分非神经营养因子类细胞因子,包括神经生长因子、睫状神经营养因子、脑源性神经生长因子、碱性成纤维生长因子、神经营养因子-3、促红细胞生成素等作一综述。     

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.     

Mesenchymal stem cells for repairing glaucomatous optic nerve

Glaucoma is a common and complex neurodegenerative disease characterized by progressive loss of retinal ganglion cells (RGCs) and axons. Currently, there is no effective method to address the cause of RGCs degeneration. However, studies on neuroprotective strategies for optic neuropathy have increased in recent years. Cell replacement and neuroprotection are major strategies for treating glaucoma and optic neuropathy. Regenerative medicine research into the repair of optic nerve damage using stem cells has received considerable attention. Stem cells possess the potential for multidirectional differentiation abilities and are capable of producing RGC-friendly microenvironments through paracrine effects. This article reviews a thorough researches of recent advances and approaches in stem cell repair of optic nerve injury, raising the controversies and unresolved issues surrounding the future of stem cells.     

Estrogen protects the inner retina from apoptosis and ischemia-induced loss of Vesl-1L/Homer 1c immunoreactive synaptic connections

PURPOSE: Protective effects of estrogen on nerve cells including retinal neurons have been described previously. However, subcellular effects on synaptic connectivity in mild ischemia more closely resembling ischemic conditions found in diabetic or sickle cell retinopathy and stenosis of the carotid artery have not been identified. The present study quantitatively analyzed effects of estrogen administration on synaptic connections of neurons in the ganglion cell layer (GCL) of the retina. METHODS: Staining of Vesl-1L/Homer 1c (V-1L) immunoreactivity and TUNEL cytochemistry were used to quantify neuroprotective effects at the synaptic level in a model of mild retinal ischemia induced by temporary middle cerebral artery occlusion in the adult rat. RESULTS: V-1L immunoreactivity was found in both synaptic layers, postsynaptic to glutamatergic ribbon synapses. Mild retinal ischemia led to a significantly higher percentage reduction in the number of V-1L-positive synapses in the inner plexiform layer (IPL) compared with the percentage of TUNEL-positive apoptotic neurons in the GCL. Estrogen prevented ischemia-induced loss of V-1L-immunoreactive synapses in the IPL and apoptosis of cells in the GCL. CONCLUSIONS: Immunoreactivity for V-1L can be used as a synaptic marker for early changes before more severe neurodegenerative events. The present results suggest that estrogen protects neurons in the GCL including RGCs from both apoptosis and early changes in synaptic connections associated with ischemia and potentially preceding apoptosis.     

Therapeutische Ansätze bei makulären Teleangiektasien Typ 2

Macular telangiectasia type 2 is characterized by neurodegenerative as well as vascular and retinal alterations. Previous therapeutic approaches mainly targeted the vascular changes; however, this did not prove to be beneficial except for secondary neovascularization which may be successfully treated with intravitreal vascular endothelial growth factor inhibitors. As the natural history of the disease is primarily characterized by the neurodegenerative processes, new therapeutic strategies, such as neuroprotective agents are already being explored in clinical trials.     

Past,present and future role of retinal imaging in neurodegenerative disease

Retinal imaging technology is rapidly advancing and can provide ever-increasing amounts of information about the structure, function and molecular composition of retinal tissue in humans in vivo. Most importantly, this information can be obtained rapidly, non-invasively and in many cases using Food and Drug Administration-approved devices that are commercially available. Technologies such as optical coherence tomography have dramatically changed our understanding of retinal disease and in many cases have significantly improved their clinical management. Since the retina is an extension of the brain and shares a common embryological origin with the central nervous system, there has also been intense interest in leveraging the expanding armamentarium of retinal imaging technology to understand, diagnose and monitor neurological diseases. This is particularly appealing because of the high spatial resolution, relatively low-cost and wide availability of retinal imaging modalities such as fundus photography or OCT compared to brain imaging modalities such as magnetic resonance imaging or positron emission tomography. The purpose of this article is to review and synthesize current research about retinal imaging in neurodegenerative disease by providing examples from the literature and elaborating on limitations, challenges and future directions. We begin by providing a general background of the most relevant retinal imaging modalities to ensure that the reader has a foundation on which to understand the clinical studies that are subsequently discussed. We then review the application and results of retinal imaging methodologies to several prevalent neurodegenerative diseases where extensive work has been done including sporadic late onset Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. We also discuss Autosomal Dominant Alzheimer's Disease and cerebrovascular small vessel disease, where the application of retinal imaging holds promise but data is currently scarce. Although cerebrovascular disease is not generally considered a neurodegenerative process, it is both a confounder and contributor to neurodegenerative disease processes that requires more attention. Finally, we discuss ongoing efforts to overcome the limitations in the field and unmet clinical and scientific needs.     

Sigma 1 receptor: A novel therapeutic target in retinal disease

Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.     

Neuroprotective effects of cardiotrophin-like cytokine on retinal ganglion cells

BACKGROUND: Premature neuronal cell death is a feature of numerous central nervous system and eye diseases, including glaucoma. Neurons (including retinal ganglion cells, RGCs) are protected by several neurotrophic factors, among those the IL-6 family of cytokines. Lately, a novel member of the IL-6 family of cytokines has been identified and cloned. This cytokine is known as novel neurotrophin-1/B-cell-stimulating factor-3 (NNT-1/BSF-3) or cardiotrophin-like cytokine (CLC). It shows neurotrophic as well as B-cell stimulatory effects. METHODS: In this study, the neuroprotective properties of CLC on RGC loss in vivo were investigated. RESULTS: CLC significantly protected RGCs from degeneration in both chosen models of retinal neuronal damage: optic nerve crush (P<0.01) and N-methyl-D-aspartate (NMDA) injection (P<0.001). CONCLUSIONS: CLC shows neuroprotective effects on RGCs in vivo and might be a treatment option for chronic neurodegenerative eye diseases such as glaucoma. Clinical feasibility for the substance requires further investigation since the immunomodulatory and possible adverse effects have not yet been thoroughly characterized.     

Quantification of amino acid neurochemistry secondary to NMDA or betaxolol application

Background: Alterations in retinal amino acid neurochemistry are an indicator of metabolic function. Glutamate is the primary excitatory amino acid neurotransmitter within the retina, and excessive levels of glutamate can potentially cause excitotoxicity, in particular, through the N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor. Anomalies in NMDA receptor function have been implicated as causing many neurodegenerative disorders, and overactivation leads to neuronal death secondary to metabolic insult. Several pharmaceutical agents have been proposed as potential neuroprotective agents against excitotoxicity (e.g. betaxolol), yet any effects such drugs have on retinal neurochemistry have not been determined. Therefore, the aim of this study was to quantify the changes in retinal amino acid neurochemistry secondary to the application of NMDA with and without betaxolol. Methods: Functional NMDA channel activation was confirmed in both amacrine and ganglion cells by quantifying the entry into these neurones of a channel permeable probe (agmatine: 1‐amino‐4‐guanidobutane [AGB]). By probing serial thin sections with immunoglobulins targeting AGB, glutamate, γ‐aminobutyric acid (GABA) and glycine, it was possible to simultaneously study the neurochemical characteristic as well as the NMDA‐evoked AGB responses of different neurochemical populations of inner retinal neurones. Results: The authors have previously shown no accumulation of glutamate or GABA within Müller cells following NMDA application. Herein they report altered GABA and glycine immunoreactivity, but not glutamate immunoreactivity within neurones of the amacrine and ganglion cell layers following NMDA application. Finally, the addition of betaxolol did not significantly alter the normal neurochemistry of the retina. Conclusion: The retina possesses intrinsic mechanisms that allow it to maintain metabolic integrity during short periods of high NMDA application.     

Dendritic changes in visual pathways in glaucoma and other neurodegenerative conditions

Visual information is sent from the retina to central visual targets through the optic nerve formed of retinal ganglion cells’ (RGCs) axons. In rodents, the superior colliculus (SC) is the major site of termination of retinal axons, whilst in primates and felines, it is the lateral geniculate nucleus (LGN). Glaucoma is a progressive optic neuropathy characterized by RGC death. There is increasing evidence that neuronal changes occur both in retina and central visual targets in glaucoma and other neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Dendrites are fine neuronal processes which support postsynaptic contact elements and are responsible for receiving synaptic signals. The morphology of dendrites has a profound impact on integrating neuronal input to the central nervous system from peripheral targets. This review summarizes different dendritic changes that have been recorded in neurodegenerative processes including those occurring in development, ageing and diseases. The findings suggest dendritic pathology is an early sign in disease and underline the importance of synapto-dendritic structure, providing new insights into therapeutic strategies.