CN113082031A - 一种多巴胺d1和d2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用 - Google Patents
一种多巴胺d1和d2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用 Download PDFInfo
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Abstract
一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用，通过激动多巴胺系统的D1和D2受体从而抑制眼部病理性血管新生，可以有效地治疗血管新生类的眼部疾病。可抑制眼部血管新生，对视网膜、角膜、脉络膜部位的新生血管都有显著的作用，可辅助治疗血管新生类眼部疾病。
Description
技术领域
本发明具体涉及病理性血管新生药物技术领域，具体涉及一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用。
背景技术
临床上，眼部新生血管包括视网膜新生血管、角膜新生血管以及脉络膜新生血管。视网膜新生血管常见于糖尿病视网膜病变、早产儿视网膜病变、视网膜中央静脉阻塞以及病理性近视等；脉络膜新生血管常见于年龄相关性黄斑变性等。正常生理条件下，血管处于促血管生成和抗血管生成因子调控下的动态平衡状态；而在缺血、缺氧或炎症等病理条件下，该动态平衡被打破，发生病理性血管新生。眼部的病理性血管新生，可引起眼部多种并发症，如玻璃体积血、纤维血管膜的形成、牵拉性视网膜脱离及黄斑出血等，造成严重的视力丧失甚至失明。
流行病学调查显示新生血管性眼病已成为全球仅次于白内障不可逆性致盲的第二大原因，且其致盲比例仍在逐年增加。临床治疗的传统方法为视网膜光凝或冷凝法，可一定程度的抑制新生血管的生成，缺点是会损害一部分视力、且效果并不持久需反复进行；现在作为一线使用的抗VEGF药物疗效较好，但也同样维持时间短、需多次注射。此外，VEGF不仅是血管生长因子，它还是一种神经营养因子，使用抗体过度消耗VEGF可能会引起视网膜血管发育迟缓等副作用。
在已有研究中，多巴胺系统可通过调节VEGF的表达来调节血管新生。因此，我们推测通过激活多巴胺系统可调控VEGF水平，抑制眼部病理性血管新生。
发明内容
为了解决现有技术存在的技术缺陷，本发明提供了一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用，通过同时激动多巴胺D1和D2受体, 找到一种抑制眼部病理性血管新生的方法。
本发明采用的技术解决方案是：一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用。
所述的眼部病理性血管新生是指视网膜新生血管、角膜新生血管和脉络膜新生血管中的一种。
所述的多巴胺D1和D2受体非选择性激动剂为阿扑吗啡（apomorphine）。
所述的药物包括药学上有效量的阿扑吗啡和药学上可接受的载体。
所述的载体选自常用的药用辅料、生理盐水或蒸馏水。
本发明的有益效果是：本发明提供了一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用，通过激动多巴胺系统的D1和D2受体从而抑制眼部病理性血管新生，可以有效地治疗血管新生类的眼部疾病。可抑制眼部血管新生，对视网膜、角膜、脉络膜部位的新生血管都有显著的作用，可辅助治疗血管新生类眼部疾病。
附图说明
图1：氧诱导视网膜病变模型(OIR)中，腹腔注射Apmorphine不影响高氧阶段的正常血管发育。A、B分别为小鼠出生后第12天高氧处理结束，溶剂ascorbic acid（Veh）和Apmorphine（APO）处理后的小鼠视网膜铺片，黄色曲线圈出无血管区。与Veh组相比，APO给药后视网膜无血管区面积无显著差异（C，独立样本t检验，P=0.50）。标尺为0.5 mm。
图2：氧诱导视网膜病变模型(OIR)中，腹腔注射Apmorphine不影响低氧阶段的正常血管发育，但抑制病理性血管新生。A、B分别为小鼠出生后第17天，溶剂ascorbic acid（Veh）和Apmorphine（APO）处理后的小鼠视网膜铺片，黄色曲线圈出无灌注区，红色圈出新生血管区。与Veh组相比，APO给药后视网膜无血管区面积无显著差异（C，独立样本t检验，P=0.35），但新生血管区面积显著下减少（D，独立样本t检验，P=0.001）。标尺为0.5 mm。
具体实施方式
Apomorphine (APO，5mg/kg，Tcris Bioscience)溶解于含有1mg/mL ascorbicacid (ICN Biomedals，Inc.，Irvine，CA，USA)的ddH2O中，以延缓氧化。以1 mg/mLascorbic acid溶液作为APO治疗的载体对照（Veh）。将同窝的C57BL/6小鼠在75%高氧环境中饲养5天后，P12天移至正常氧环境下继续饲养。在高氧环境中，从P7天开始每天腹腔给药Apmorphine（5 mg/kg）或溶剂对照ascorbic acid（1 mg/ml），至P12天取材；在相对低氧阶段（P12-P17），从P12天开始每天腹腔给药Apmorphine（5mg/kg）或溶剂对照ascorbic acid（1 mg/ml），至P17天取材。各组注射量均为10mL/kg。
在高氧阶段，APO组较Veh组，视网膜无血管区的面积无变化（Veh vs APO: 34.07%±2.73% vs 32.96% ± 2.98%, P = 0.50, independent t-test）；在相对的低氧阶段，APO组较Veh组，视网膜无血管区的面积无变化（Veh vs APO: 19.35% ± 2.01% vs 20.52%± 3.09%, P = 0.35, independent t-test），而病理性新生血管的面积显著减少（Veh vsAPO: 9.64% ± 1.22% vs 6.91% ± 1.74%, P = 0.001, independent t-test（图2）。证明多巴胺激动剂不影响小鼠视网膜血管的正常发育，但在OIR模型的相对低氧阶段抑制了病理性新生血管的形成。
上述实验标明，APO激动多巴胺系统在不影响正常血管发育的同时，可抑制眼部血管新生，提示多巴胺激动剂对视网膜、角膜、脉络膜部位的新生血管有抑制作用，可辅助治疗血管新生类眼部疾病。
各位技术人员须知：虽然本发明已按照上述具体实施方式做了描述，但是本发明的发明思想并不仅限于此发明，任何运用本发明思想的改装，都将纳入本专利专利权保护范围内。
以上所述仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种多巴胺D1和D2受体非选择性激动剂在作为制备治疗眼部病理性血管新生药物的应用。
2.根据权利要求1所述的应用，其特征在于，所述的眼部病理性血管新生是指视网膜新生血管、角膜新生血管和脉络膜新生血管中的一种。
3.根据权利要求1所述的应用，其特征在于，所述的多巴胺D1和D2受体非选择性激动剂为阿扑吗啡（apomorphine）。
4.根据权利要求3所述的应用，其特征在于，所述的药物包括药学上有效量的阿扑吗啡和药学上可接受的载体。
5.根据权利要求4所述的应用，其特征在于，所述的载体选自常用的药用辅料、生理盐水或蒸馏水。
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