CN109303782A - Jnk-in-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用 - Google Patents
Jnk-in-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用 Download PDFInfo
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- CN109303782A CN109303782A CN201811242480.7A CN201811242480A CN109303782A CN 109303782 A CN109303782 A CN 109303782A CN 201811242480 A CN201811242480 A CN 201811242480A CN 109303782 A CN109303782 A CN 109303782A
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Abstract
本发明公开了JNK‑IN‑8在制备干性年龄相关性黄斑变性的神经保护剂中的应用，JNK‑IN‑8通过特异性阻断JNK信号通路，抑制感光细胞死亡，维持了视网膜的完整性，从而起到保护视网膜的作用。由于JNK‑IN‑8在动物实验中可以有效透过血视网膜屏障，治疗作用疗效明显，且给药方便，无明显毒副作用，因此JNK‑IN‑8在治疗干性AMD疾病的药物开发方面具有广阔的前景。
Description
技术领域
本发明属于黄斑变性类疾病神经保护剂药物技术领域，具体涉及JNK抑制剂JNK-IN-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用。
背景技术
世界卫生组织(WHO)的数据显示，黄斑变性类疾病特别是年龄相关性黄斑变性(age-related macular degeneration，AMD)是全球继白内障和青光眼之后第三大致盲眼病，也是造成我国50岁以上人群失明的首要原因。根据临床表现的不同，AMD分为湿性AMD和干性AMD两类。其中，湿性AMD主要表现为脉络膜新生血管，目前临床上已经可以采用抗VEGF药物如培加他尼(Pegaptanib)、雷珠单抗(Ranibizumab)、贝伐单抗(Bevacizumab)、阿柏西普(Aflibercept)、康柏西普(Conbercept)等进行治标性治疗。然而90％的AMD患者是干性AMD，在干性AMD的早期，可以观察到视网膜色素上皮细胞(retinal pigment epithelium，RPE)外有玻璃疣的产生。随着疾病的不断发展，玻璃疣的体积不断增大，同时RPE中出现脂褐素沉积。在疾病的晚期，黄斑区的RPE细胞退化死亡，导致黄斑区的感光细胞大量死亡，从而引起中心视力以及视觉灵敏度的丧失，称为地图样萎缩(geographic atrophy，GA)。干性AMD造成视力不可逆损伤的关键原因在于黄斑区感光细胞的死亡。感光细胞是一类特殊的神经元细胞，是视网膜中将光信号转换为电信号的关键。作为神经元细胞，感光细胞死亡后无法再生，使得干性AMD的治疗更为困难。最新的研究显示，在湿性AMD患者中，当抗VEGF药物控制住脉络膜新生血管后，视网膜会继发出现干性AMD样的病理改变。不同于湿性AMD，干性AMD依然尚无有效的治疗药物和方法。
干性AMD的病理生理学机制至今依然不清晰，与之相关的风险因素包括年龄、吸烟、高血压、高血脂、腹部肥胖、高脂饮食和缺乏锻炼等。目前正在进行研究的治疗措施和药物包括：1、饮食调节：AREDS(age-related eye disease study)研究小组采用一个特殊的饮食补充方法(每天服用80毫克氧化锌、2毫克氧化铜、15毫克β-胡萝卜素、50毫克维他命C和400单位维他命E)治疗发病阶段的干性AMD患者。这种饮食补充方法仅在一部分高风险携带疾病危险基因突变的干性AMD患者中具有抑制疾病发展的作用，但是在大多数患者中并未表现出应有的治疗缓解效果；2、神经保护类药物：主要包括两类(1)溴莫尼定(brimonidine)：溴莫尼定是α2受体的激动剂，最先被用于青光眼患者保护视网膜的神经元细胞，已有临床II期试验用于验证该药物在GA患者中的神经保护作用；(2)睫状节神经细胞营养因子(ciliary neurotrophic factor-501，CNTF)：是一种IL-6细胞因子，在动物模型中显示对视网膜具有保护作用。已有临床II期试验采用缓释系统NT-501和CNTF联合治疗GA患者，一年后随访发现具有一定的保护效果。3、针对炎症的治疗药物：(1)Iluvien：针对GA中的慢性炎症，美国Alimera Sciences公司正进行临床II期试验研究缓释制剂醋酸氟轻松的效果，目前结果仍不明朗；(2)针对干性AMD中补体激活现象，一些抑制补体激活的单克隆抗体药物如lampalizumab正在进行临床试验，在II期试验中显示出一定的GA治疗效果，但是抗体类药物普遍存在给药方式复杂，无法长期重复给药，可能引起眼内炎等严重并发症的缺点；(3)ARC1905：C5基因的DNA核酸适配体，在I期临床试验中证明其安全性，但是其有效性仍需要进一步确认；(4)POT-4：C3的抑制剂，已通过I期临床试验证明其安全性。4、血管扩张剂：针对在老年AMD患者中脉络膜血流供给下降的现象，采用血管扩张剂来增加营养供给，延缓视网膜退化，包括(1)前列地尔(Alprostadil)已经通过临床III期试验，证实经过6月的治疗与安慰剂相比具有延缓视网膜功能退化的作用；(2)西地那非(Sildenafil)和莫沙维林(Moxaverine)：非选择性的磷酸二酯酶的抑制剂，但是其临床效果尚不明确。5、针对视觉循环的治疗药物：(1)依舒司他(Emixustat)是一种非类视色素的是视觉循环异构酶RPE65的调节剂，已经通过II期临床试验；(2)视觉循环的抑制剂维甲酰酚胺(Fenretinide)也正在研究中，它的有效性还没有在患者中进行验证。但是，所有的视觉循环调节剂都由于影响视觉循环，可能引起夜盲等副作用。6、干细胞疗法：目前已有研究采用干细胞分化为RPE和感光细胞治疗干性AMD，但是它们的有效性和安全性还需要长期的验证。
JNK-IN-8(CAS No：1410880-22-6，分子式：C29H29N7O2，分子量：507.59，其分子式如上式所示)是化学合成的化合物，是一种特异性、不可逆的JNK抑制剂，通过与JNK的保守的半胱氨酸的ATP位点共价结合，从而抑制JNK激酶的活性，降低磷酸化c-Jun的蛋白水平。研究表明，JNK信号通路是多种疾病包括癌症、糖尿病等的潜在治疗靶点。已有研究显示JNK-IN-8在人类黑色素瘤细胞中具有抑制细胞增殖和诱导细胞死亡的作用，在三重阴性乳腺癌细胞中，JNK-IN-8可以有效抑制肿瘤干细胞的表型从而限制小鼠模型中的肿瘤生长。也有研究显示在小鼠黑质纹状体通路损伤模型中，JNK-IN-8可以通过抑制JNK1/2/4的活性有效保护神经元细胞并降低炎症因子的释放。在缺氧再灌注的心肌损伤模型中，JNK-IN-8可以抑制NF-κB的磷酸化，从而抑制其激活及下游炎症因子的产生。同时也有研究显示JNK-IN-8作为基因靶点药物，可以有效提高机体自身免疫系统抵抗真菌感染的能力，可用于抗真菌药物的研发。再者，在细胞的去分化及分化成为血管内皮细胞、血管平滑肌细胞、成骨细胞、软骨细胞中，均有报道JNK-IN-8可作为调节剂促进细胞命运的转换。但目前还未有JNK信号通路与干性年龄相关性黄斑变性相关以及JNK-IN-8可作为干性年龄相关性黄斑变性的神经保护剂的报道。
发明内容
本发明的目的在于克服现有技术的不足之处，提供了JNK抑制剂JNK-IN-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用。
本发明解决其技术问题所采用的技术方案是：
JNK-IN-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用。所述神经保护剂是指能够减少病理状况下的应激反应、降低炎症损伤、促进神经细胞的再生和修复等的一类药物。
一实施例中：所述应用是指防止地图样萎缩发生。
一实施例中：所述应用是指保护视网膜、改善视网膜损伤或维持视网膜完整性。
一实施例中：所述应用是指保护视网膜感光细胞，防止视网膜感光细胞退化或死亡。
一实施例中：所述保护视网膜感光细胞是指维持视网膜感光细胞外节正常形态和长度。
一实施例中：所述保护视网膜感光细胞是指维持视网膜感光细胞外核层正常形态和厚度。
一实施例中：所述应用是指防止视网膜的凋亡。
一实施例中：所述应用是通过抑制JNK信号通路进行。
一实施例中：所述JNK-IN-8的给药方式包括腔内给药、静脉给药、皮下给药、口服给药。
本技术方案与背景技术相比，它具有如下优点：
在干性AMD疾病特征中，RPE细胞退化最终导致感光细胞的死亡。JNK-IN-8通过特异性阻断JNK信号通路，抑制感光细胞死亡，维持了视网膜的完整性，从而起到保护视网膜的作用。由于JNK-IN-8在动物实验中可以有效透过血视网膜屏障，治疗作用疗效明显，且给药方便，无明显毒副作用，因此JNK-IN-8在治疗干性AMD疾病的药物开发方面具有广阔的前景。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为JNK-IN-8对光照后Abca4-/-Rdh8-/-双敲小鼠视网膜的HE染色图片。
图2为JNK-IN-8通过抑制JNK信号通路减轻光照后Abca4-/-Rdh8-/-双敲小鼠视网膜受到的损伤。
具体实施方式
下面通过实施例具体说明本发明的内容：
实施例
实验设计：JNK-IN-8溶解于DMSO中配成10mg/mL母液。依次将纯溶剂加入母液中，现配现用：2％DMSO+30％PEG 300+5％Tween 80+ddH2O。
动物模型：全反式视黄醛过量累积会造成RPE细胞和感光细胞的损伤退化。视觉循环中全反式视黄醛(all-trans-retinaldehyde，atRAL)的异常代谢是AMD发生的一个关键因素之一。在最常见的遗传类黄斑变性类疾病Stargardt病中Abca4基因的突变是导致青少年黄斑变性的最主要原因。ABCA4、RDH8是视觉循环中使atRAL重生为11-cis-RAL两个关键的蛋白，Abca4-/-Rdh8-/-双敲小鼠表现出atRAL清除障碍，并出现RPE细胞退化、感光细胞死亡、脂褐素积聚、补体激活等现象。同时，有研究发现对Abca4-/-Rdh8-/-双敲小鼠进行光照后，其表现出快速的感光细胞退化表型，可以作为筛选开发AMD视网膜感光细胞保护剂的优良模型。
本实施例选择4～5周龄的Abca4-/-Rdh8-/-双敲小鼠作为实验对象，JNK-IN-8实验组小鼠按照5mg/kg体重进行腹腔注射，对照组按照等量的溶剂进行腹腔注射。注射后1小时，用10K lux的白光对小鼠进行光照2小时。在光照之前，用托吡卡胺滴眼液对小鼠眼睛进行散瞳处理。光照后1天(D1)、3天(D3)、5天(D5)处死小鼠取眼球进行分析。
如图1所示，在Abca4-/-Rdh8-/-双敲小鼠的光照损伤模型中，JNK-IN-8处理对视网膜具有明显的保护作用。Abca4-/-Rdh8-/-双敲小鼠在10K lux光照后溶剂处理组D1、D3、D5均出现了明显的损伤现象，感光细胞的外节和外核层明显变薄，外核层细胞核散乱分布等视网膜退化现象，然而在JNK-IN-8处理组，小鼠的视网膜有明显的恢复，感光细胞的外节和外核呈现了正常的形态，表明JNK-IN-8处理对Abca4-/-Rdh8-/-双敲小鼠受到的光照损伤具有明显的改善作用。
如图2所示，Abca4-/-Rdh8-/-双敲小鼠在10K lux光照后，TUNEL染色结果发现Abca4-/-Rdh8-/-双敲小鼠的神经视网膜在10K lux光照后有明显的凋亡。检测神经视网膜中凋亡相关的蛋白RIP1、Bax以及p-JNK的表达呈现出明显上升的现象，进一步说明Abca4-/-Rdh8-/-双敲小鼠在光照后神经视网膜有凋亡现象，但是JNK-IN-8处理后RIP1、Bax、p-JNK的蛋白水平下降，说明JNK-IN-8通过抑制JNK信号通路保护光照后Abca4-/-Rdh8-/-双敲小鼠视网膜受到的损伤凋亡。
以上所述，仅为本发明较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。
Claims (9)
1.JNK-IN-8在制备干性年龄相关性黄斑变性的神经保护剂中的应用。
2.根据权利要求1所述的应用，其特征在于：所述应用是指防止地图样萎缩发生。
3.根据权利要求1所述的应用，其特征在于：所述应用是指保护视网膜、改善视网膜损伤或维持视网膜完整性。
4.根据权利要求1所述的应用，其特征在于：所述应用是指保护视网膜感光细胞，防止视网膜感光细胞退化或死亡。
5.根据权利要求4所述的应用，其特征在于：所述保护视网膜感光细胞是指维持视网膜感光细胞外节正常形态和长度。
6.根据权利要求4所述的应用，其特征在于：所述保护视网膜感光细胞是指维持视网膜感光细胞外核层正常形态和厚度。
7.根据权利要求1所述的应用，其特征在于：所述应用是指防止视网膜的凋亡。
8.根据权利要求1所述的应用，其特征在于：所述应用是通过抑制JNK信号通路进行。
9.根据权利要求1所述的应用，其特征在于：所述JNK-IN-8的给药方式包括腔内给药、静脉给药、皮下给药、口服给药。
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