CN111760016A - 卡泊芬净在制备神经保护药物中的应用 - Google Patents
卡泊芬净在制备神经保护药物中的应用 Download PDFInfo
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Abstract
本发明涉及卡泊芬净在制备神经保护药物中的应用，属生物医药领域。本发明发现卡泊芬净用于抑制或治疗神经元或轴突变性，尤其是用于治疗视觉相关神经变性和神经系统病症，更尤其是对视觉相关性神经变性的保护作用，能显著减轻视神经节细胞和轴突损伤，具有保护神经细胞功能。
Description
技术领域
本发明涉及卡泊芬净在制备神经保护药物中的应用，属于生物医药领域。
背景技术
神经元或轴突变性是很多神经变性疾病的标志，神经变性疾病包括青光眼、视网膜色素变性、年龄相关黄斑病变、视网膜脱离、肌萎缩侧索硬化、阿尔茨海默氏病、帕金森病、以及对脑和脊髓的创伤性损伤等疾病。神经变性疾病和损伤对于患者及其家庭都是巨大的，并导致的经济负担，开发有效方法以治疗神经变性疾病和神经系统损伤具有重要的意义。
青光眼为全球不可逆性盲眼病之首，其主要危险因素及发病特点是病理性的眼压增高和视网膜神经节细胞变性和进行性死亡，以及视网膜神经节细胞轴突变性减少。视网膜神经节细胞没有分裂和再生能力，因此视神经损伤不可逆。因此，阻止视网膜神经节细胞的进行性丢失，是阻止患者的视力恶化的有效途径。目前，床上青光眼的治疗主要通过药物、激光及手术来降低和控制眼压，对于视网膜神经节细胞的保护处于起步阶段，目前尚未有明显保护效果的药物。
卡泊芬净为棘白菌素类抗真菌药，棘白菌素类抗真菌药能抑制真菌细胞壁生成，通过非竞争性抑制葡聚糖合成酶，导致真菌细胞生长过程中细胞壁葡聚糖缺乏，渗透压失常，最终产生真菌细胞溶解。卡泊芬净对于念珠菌、曲霉菌等有良好的抑制活性，目前主要用于侵袭性曲霉菌的治疗，不良反应少，但是否具有抑制轴突和神经元变性作用尚未见报道。
发明内容
针对现有技术的不足，本发明的目的在于提供卡泊芬净在制备神经保护药物中的应用。
为了解决上述技术问题，本发明的技术方案如下：
卡泊芬净在制备神经保护药物中的应用。
进一步地，所述神经保护药物是治疗/预防神经变性疾病/神经细胞损伤的药物。
卡泊芬净在制备治疗/预防神经变性疾病/神经细胞损伤的药物中的应用。
本发明中，“治疗/预防”表示“治疗和/或预防”；“神经变性疾病/神经细胞损伤”表示“神经变性疾病和/或神经细胞损伤”。
可选的，本发明的卡泊芬净的结构式如下所示
进一步地，所述神经变性疾病包括视神经变性疾病和中枢神经细胞疾病。
进一步地，所述神经细胞为视网膜神经节细胞。
进一步地，所述神经细胞包括中枢神经系统疾病相关神经细胞。
进一步地，卡泊芬净及可用于抑制/治疗神经元/轴突变性的应用。因此，所述药物用于治疗，例如，①视觉相关神经变性；②神经系统病症(例如，神经变性疾病)；③继发于对神经系统外部具有主要影响的疾病；④机械的、物理的或化学的创伤引起的神经系统损伤；⑤疼痛；⑥记忆丧失；⑦精神病症。这些疾病、病症和损伤的非限制性实例如下：
进一步地，所述神经变性疾病包括青光眼、色素变性、角膜网络状营养不良、年龄相关性黄斑变性(AMD)、湿性或干性AMD相关光感受器变性、视神经病变、视神经炎、视神经玻璃疣、阿尔茨海默氏病、帕金森病、亨廷顿病、帕金森叠加综合症、局部缺血、肌萎缩侧索硬化(ALS)、颅内出血、脑出血、三叉神经痛、舌咽神经痛、重症肌无力、肌肉萎缩症、进行性肌萎缩症、贝尔麻痹、进行性延髓麻痹、脊髓性肌萎缩、原发性侧索硬化(PLS)、假性延髓麻痹、无脊椎动物盘综合征、颈椎病、遗传性肌萎缩、周围神经病变、由暴露于选自由工业溶剂、重金属、药物和化疗剂组成的组中的毒性化合物引起的神经损伤、由机械的、物理的或化学的创伤引起的神经系统损伤中的一种或几种。可选的，所述视网膜变性为视网膜色素变性。
进一步地，所述神经变性疾病包括青光眼、视网膜色素变性、角膜网络状营养不良、年龄相关性黄斑变性(AMD)、湿性或干性AMD相关光感受器变性中的一种或几种。
进一步地，所述神经变性疾病包括阿尔茨海默氏病、帕金森病和肌萎缩侧索硬化(ALS)中的一种或几种。
进一步地，所述应用中，给药通过选自由以下各项组成的给药途径进行：肠胃外、皮下、腹膜内、静脉内、病灶内、脑内、肌肉内、眼内、玻璃体腔注射、动脉内间质输注和植入的递送装置。
可选的，所述应用中的给药方式为玻璃体腔注射给药。
可选的，可将卡泊芬净制备成药剂学上可以接受的任意一种剂型。
可选的，所述剂型包括注射剂、胶囊剂、片剂、颗粒剂、喷雾剂、散剂、口服液、滴丸中的一种。
本发明人在离体细胞药物筛选过程中，发现卡泊芬净能降低N-甲基-D-天门冬氨酸(NMDA)诱导的小鼠视神经节细胞(RGC)死亡和轴突变性减少。
本发明通过实验首次表明，卡泊芬净可显著减轻小鼠青光眼视神经节细胞死亡和轴突变性减少。因此，卡泊芬净能用于制备预防和治疗视觉相关神经变性和相关疾病和病症，具有良好的开发应用前景。
本发明扩大了卡泊芬净的适应症，可适用于神经变性疾病和神经细胞损伤。
本发明发现卡泊芬净用于抑制或治疗神经元或轴突变性，尤其是用于治疗视觉相关神经变性和神经系统病症，更尤其是对视觉相关性神经变性的保护作用，能显著减轻视神经节细胞和轴突损伤，有效保护神经细胞。
本发明涉及的卡泊芬净在制备治疗/预防神经变性疾病/神经细胞损伤药物中的应用，属于首次公开，对于可显著降低神经细胞和轴突变性死亡，是意想不到的，与卡泊芬净的已知用途毫不相关，也不存在现有其他化合物给出相关启示，具备突出的实质性特点，用于治疗或预防神经变性疾病或神经细胞损伤具有显著的进步。
总之，本发明将卡泊芬净用于治疗/预防神经变性疾病/神经细胞损伤，尤其是对青光眼的保护作用，能显著减轻视网膜神经节细胞损伤和轴突变性减少，保护神经细胞。
附图说明
图1为小鼠视网膜全铺片视网膜神经节细胞Brn3a免疫荧光组化染色结果。
图2为小鼠视网膜神经节细胞数量统计图。
具体实施方式
以下说明描述了本发明的可选实施方式以教导本领域普通技术人员如何实施和再现本明。为了教导本发明技术方案，已简化或省略了一些常规方面。
以下通过实验来进一步说明其药物活性。
动物实验：卡泊芬净对NMDA诱导青光眼模型鼠的保护作用。
实施药品：卡泊芬净购于试剂公司。
将卡泊芬净用DMSO溶解。
实验动物：
选取6-8周C57健康雄性小鼠。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验要求，玻璃体腔注射给药.
建模方法：
采用Hamilton 33G尖针沿角膜巩膜缘斜行45度进针，进针深度3mm，针尖指向视乳头，缓慢推注NMDA稀释液20mM，推注完毕后停留20s，缓慢拔针。每只C57小鼠选右眼为实验眼，左眼为自身对照。5天结束后行全视网膜铺片查看神经节细胞数量可判断模型是否成功，行全视网膜铺片视网膜神经节细胞Brn3a免疫荧光组化染色，按照每个象限2个部位行视网膜神经节细胞和轴突计数，观察视网膜神经节细胞数量差异和轴突数量多少及完整性。
实验分组：
对照组(假手术组)：6-8周C57雄性小鼠，玻璃体腔注射与模型组等体积PBS+DMSO
NMDA组(模型组)：6-8周C57雄性小鼠，玻璃体腔注射浓度为20mM的NMDA1uL(含与药物组相同浓度的DMSO)诱导青光眼模型。
NMDA+卡泊芬净组：6-8周C57雄性小鼠，玻璃体腔注射20mM NMDA+5uM卡泊芬净1ul。
免疫荧光组化染色：
将实验组小鼠在造模5天后，予以腹腔注射过量麻药的方法处死小鼠，无菌条件下按步骤摘除小鼠眼球，立即置于冰上。将眼球置于多聚甲醛中固定1小时，PBS冲洗后，在手术显微镜下矢状面于两侧角膜缘处迅速作一环行切口，去除晶状体，并置于30％蔗糖溶液脱水过夜。
将去除了角膜及晶状体的眼球取出，放入新鲜蔗糖溶液，于干冰中冻融3次，每次3分钟。将眼球于PBS中冲洗3次，每次10分钟，之后将眼球置于1％BSA与0.1％Triton X-100中室温中封闭1 小时。将眼球置于Brn3a单克隆抗体4℃过夜。水平摇床上洗3次，每次20分钟。滴加荧光标记二抗，室温避光孵育2h,水平摇床上洗3次，每次20分钟。手术显微镜下取下视网膜，进行铺片,神经层向上，滴少许抗荧光催灭剂封片，于荧光显微镜下观察并照相。
实验结果：
卡泊芬净对NMDA诱导的视网膜神经节细胞损伤的保护作用
参见图1和图2，NMDA组小鼠视网膜神经节细胞明显减少(Brn3a免疫荧光组化染色)，而给予卡泊芬净组视神经节细胞明显比NMDA组多，其中，图1为小鼠视网膜全铺片视网膜神经节细胞 Brn3a免疫荧光组化染色结果；图2为小鼠视网膜神经节细胞数量统计图。数据表示为均数±标准差， n＝4，###P＜0.001vs对照组，***P＜0.001vsNMDA组。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明，而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (8)
1.卡泊芬净在制备神经保护药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述神经保护药物是治疗/预防神经变性疾病/神经细胞损伤的药物。
3.根据权利要求2所述的应用，其特征在于，所述神经变性疾病包括视神经变性疾病和中枢神经细胞疾病。
4.根据权利要求2所述的应用，其特征在于，所述神经细胞为视网膜神经节细胞。
5.根据权利要求2所述的应用，其特征在于，所述神经细胞包括中枢神经系统疾病相关神经细胞。
6.根据权利要求2所述的应用，其特征在于，所述神经变性疾病包括青光眼、色素变性、角膜网络状营养不良、年龄相关性黄斑变性、湿性或干性AMD相关光感受器变性、视神经病变、视神经炎、视神经玻璃疣、阿尔茨海默氏病、帕金森病、亨廷顿病、帕金森叠加综合症、局部缺血、肌萎缩侧索硬化、颅内出血、脑出血、三叉神经痛、舌咽神经痛、重症肌无力、肌肉萎缩症、进行性肌萎缩症、贝尔麻痹、进行性延髓麻痹、脊髓性肌萎缩、原发性侧索硬化、假性延髓麻痹、无脊椎动物盘综合征、颈椎病、遗传性肌萎缩、周围神经病变、由暴露于选自由工业溶剂、重金属、药物和化疗剂组成的组中的毒性化合物引起的神经损伤、由机械的、物理的或化学的创伤引起的神经系统损伤中的一种或几种。
7.根据权利要求6所述的应用，其特征在于，所述神经变性疾病包括青光眼、视网膜色素变性、角膜网络状营养不良、年龄相关性黄斑变性、湿性或干性AMD相关光感受器变性中的一种或几种。
8.根据权利要求6所述的应用，其特征在于，所述神经变性疾病包括阿尔茨海默氏病、帕金森病和肌萎缩侧索硬化中的一种或几种。
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