CN103948601A - 3-甲基腺嘌呤在制备治疗动脉粥样硬化及其相关疾病的药物中的应用 - Google Patents
3-甲基腺嘌呤在制备治疗动脉粥样硬化及其相关疾病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了3-甲基腺嘌呤在制备治疗动脉粥样硬化及其相关疾病的药物中的应用，本发明通过试验证明：溶解于磷酸盐缓冲液中的低浓度3-MA对机体没有毒性，并且治疗动脉粥样硬化治疗效果明显。研究发现：给高脂喂养的Apoe-/-小鼠腹腔注射3-MA，既可有效抑制动脉粥样硬化斑块的形成，又可提高动脉粥样硬化斑块的稳定性。因此，可以预期，3-MA可以用于治疗动脉粥样硬化及其相关疾病，3-MA可成为一种防治动脉粥样硬化及其相关疾病的新药，可以用于制备治疗或预防动脉粥样硬化及其相关疾病的药物，如，冠心病、心肌梗死、脑中风、动脉瘤、动脉硬化症等。
Description
技术领域
本发明涉及3-甲基腺嘌呤(3-Methyladenine，3-MA)在制备治疗动脉粥样硬化及其相关疾病的药物中的应用，具体地说是3-甲基腺嘌呤在治疗动脉粥样硬化临床上的应用和制备动脉粥样硬化相关疾病药物方面的应用。
背景技术
动脉粥样硬化(Atherosclerosis，As)是一种血管壁的慢性炎症性疾病，在成年人中具有很高的发病率和致死率，是危害人类健康的主要疾病之一。目前，动脉血管壁的内皮损伤及内膜下脂质沉积被认为是As发生的使动因素。其发病的基本过程如下：高血压、高脂血症等刺激血管内皮细胞受损后使细胞功能改变和渗透性增高，导致血液中的脂质在内皮下沉积。随后血液中的单核细胞在黏附分子的介导下由损伤处进入内皮下，变为巨噬细胞后吞噬脂质，大量荷脂的巨噬细胞会变成泡沫细胞，形成脂肪斑。病灶发生处的内皮细胞、巨噬细胞和血小板释放的炎性因子和生长因子会刺激平滑肌细胞迁移入内膜，平滑肌细胞增生并合成胶原纤维形成纤维帽，使脂肪斑演变成纤维斑块。脂质的进一步积累和炎性细胞浸润会导致纤维帽变薄，形成不稳定斑块。不稳定斑块的破裂最终导致心脑血管的严重损害。
鉴于As发病各阶段的演变机制十分复杂，人们对As的研究已有百余年的历史，随着人们对As了解的不断深入，抗As的药物也在不断发展。针对As发生的主要影响因素，抗血小板类药物、血脂调节类药物、抗脂质氧化剂等逐渐成为抗As的主要临床用药。
近年来越来越多的文章表明自噬与As的发生发展有关。As发生发展过程中产生的氧化低密度脂蛋白、炎症反应和代谢应激反应都可以刺激细胞自噬水平升高。3-甲基腺嘌呤(3-Methyladenine，3-MA)是一种应用广泛的细胞自噬抑制剂。它可以通过抑制III型磷脂酰肌醇3磷酸激酶(ClassIIIPI3K)的活性来抑制细胞内自噬体的形成。近年来有文章报道在某些条件下，3-MA可以通过抑制I型磷脂酰肌醇三磷酸对自噬的发生起到促进的作用。但体内对动脉粥样硬化是否有防治作用，未见报道。
发明内容，
针对上述现有技术，本发明的目的是探究3-MA对As的作用，达到治疗As的目的。
本发明的研究采用3-MA治疗小鼠动脉粥样硬化，通过试验证明：低浓度溶解于细胞PBS的3-MA治疗动脉粥样硬化治疗效果明显并且对机体没有毒性。研究发现：给高脂喂养的Apoe-/-小鼠同时腹腔注射3-MA不仅可抑制动脉粥样硬化斑块的形成，而且可改善斑块的稳定性。因此，可以预期，3-MA及其衍生物可以用于治疗动脉粥样硬化及其相关疾病，可以用于制备治疗或预防动脉粥样硬化及其相关疾病的药物，如，冠心病、心肌梗死、脑中风、动脉瘤、动脉硬化症等。
所述3-甲基腺嘌呤衍生物是指在3-甲基腺嘌呤基础上进行各种修饰后得到的物质。所述各种修饰包括在3-甲基腺嘌呤上用添加不同的化学基团或用不同的化学基团取代原有基团。
本发明所产生的积极效果是：(1)3-MA具有减小小鼠主动脉As斑块面积的作用；(2)3-MA可以很好地降低As斑块内脂质含量；(3)3-MA可以很好地减小斑块内坏死核心，增加纤维帽的厚度，稳定斑块；(4)3-MA是一种化学药物，合成容易，成本低，体外稳定易保存；(5)由于动脉粥样硬化的发病率高，市场前景广泛。
本发明采用3-MA治疗小鼠动脉粥样硬化，可明显抑制动脉粥样硬化斑块的形成和易损性，取得了较好的效果。国内外文献尚未见3-MA治疗动脉粥样硬化及其相关疾病的报道，因此，3-MA可成为一种防治动脉粥样硬化及其相关疾病的新药。
附图说明
图1：3-MA治疗组和对照组Apoe-/-小鼠腹主动脉斑块油红O染色示意图，其中，a：腹腔注射PBS的对照组Apoe-/-小鼠腹主动脉有明显的斑块；b：腹腔注射3-MA的治疗组Apoe-/-小鼠腹主动脉斑块面积显著减少。
图2：3-MA治疗组和对照组Apoe-/-小鼠腹主动脉斑块面积统计示意图。
图3：3-MA治疗组和对照组Apoe-/-小鼠主动脉根部斑块HE染色示意图，其中，a：对照组Apoe-/-小鼠主动脉根部有明显斑块；b：3-MA治疗组Apoe-/-小鼠主动脉根部斑块明显减小。
图4：3-MA治疗组和对照组Apoe-/-小鼠主动脉根部斑块面积统计示意图。
图5：3-MA治疗组和对照组Apoe-/-小鼠主动脉根部斑块脂质ORO染色示意图，其中，a：对照组Apoe-/-小鼠主动脉根部斑块含有大量脂质；b：3-MA治疗组Apoe-/-小鼠主动脉根部斑块脂质含量降低。
图6：3-MA治疗组和对照组Apoe-/-小鼠主动脉根部斑块脂质含量统计示意图。
图7：3-MA治疗组和对照组Apoe-/-小鼠主动脉根部斑块TUNEL染色示意图，其中，a：对照组Apoe-/-小鼠主动脉根部斑块内有大量凋亡细胞和明显的坏死核心；b：3-MA治疗组Apoe-/-小鼠主动脉根部斑块内凋亡细胞减少。
具体实施方式
下面结合实施例对本发明作进一步的说明。
实施例13-MA对小鼠动脉粥样硬化的影响
取8w雄性Apoe-/-小鼠,体重22-24g,随机分为(1)高脂喂养对照组(高脂喂养10周,腹腔注射生理盐水)；(3)3-MA治疗组(在高脂喂养10周期间每周两次腹腔注射3-MA30mg/kg，3-MA用细胞PBS溶解)。每组15只小鼠,连续治疗10周。
试验结果
1.动脉粥样硬化模型：
高脂喂养10周的Apoe-/-小鼠相比于非高脂喂养的Apoe-/-小鼠，体态肥大，不活泼，皮毛稀疏油腻。大体染色和主动脉根冰冻切片结果显示高脂喂养Apoe-/-小鼠主动脉壁有明显斑块生成。
2.使用3-MA治疗动脉粥样硬化疗效观察：
1)血液常规检查
用高脂喂养10周的Apoe-/-小鼠作为对照，3-MA治疗组小鼠的体重和血清中甘油三酯(TGs)、胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、谷丙转氨酶、肌酐、尿素氮无显著差别(见表1)，3-MA治疗组小鼠血清中谷草转氨酶水平明显低于对照组小鼠，更接近正常水平。
表1
2)斑块面积
用高脂喂养10周的Apoe-/-小鼠作为对照，主动脉大体染色显示3-MA治疗组小鼠主动脉弓、胸主动脉、腹主动脉处斑块显著减少(见图1、图2)。主动脉根部冰冻切片的HE染色结果显示3-MA治疗组小鼠主动脉根部斑块面积显著减小(见图3、图4)。
3.斑块脂质含量
用高脂喂养10周的Apoe-/-小鼠作为对照，主动脉根部冰冻切片的油红O(OilredO，ORO)染色结果显示3-MA治疗组小鼠主动脉根部斑块内脂质含量显著减少(见图5、图6)，提示3-MA可能具有降低斑块内脂质含量的潜能。
4.斑块内细胞凋亡检测
用高脂喂养10周的Apoe-/-小鼠作为对照，主动脉根部冰冻切片的TUNEL染色结果(见图7)显示3-MA治疗组小鼠主动脉根部斑块坏死核心显著减小。提示3-MA治疗动脉粥样硬化相关疾病病，不仅可以降低斑块内部脂质，而且减少坏死核心形成，将是一种值得关注的治疗方案。
通过上述研究证明：
1.低剂量的3-MA持续作用对动物机体无明显损伤。
2.3-MA具有减小斑块面积、减低斑块脂质含量、减小坏死核心的作用。提示骨3-MA对动脉粥样硬化的影响将是一种值得关注的治疗方案，对动脉粥样硬化的治疗有重要价值，同时是研究制备根治动脉粥样硬化及其相关疾病新药的基础。
Claims (6)
1.3-甲基腺嘌呤或其衍生物在制备治疗动脉粥样硬化及其相关疾病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述动脉粥样硬化相关疾病包括冠心病、心肌梗死、脑中风、腹主动脉瘤、动脉硬化症。
3.根据权利要求2所述的应用，其特征在于：所述冠心病包括稳定性心绞痛、不稳定性心绞痛。
4.根据权利要求2所述的应用，其特征在于：所述脑中风包括脑出血、脑梗死。
5.根据权利要求1所述的应用，其特征在于：所述3-甲基腺嘌呤衍生物是指在3-甲基腺嘌呤基础上进行各种修饰后得到的物质。
6.根据权利要求5所述的应用，其特征在于：所述各种修饰包括在3-甲基腺嘌呤上用添加不同的化学基团或用不同的化学基团取代原有基团。
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| Title |
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| AI TAKEDA-WATANABE等: "SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》, no. 427, 31 December 2012 (2012-12-31), pages 191 - 196 * |
| 刘汴生: "《衰老与老年病防治研究》", 31 October 2009, article "十、预后", pages: 479 * |
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