CN114869878B - 表儿茶素没食子酸酯在制备治疗高原脑水肿药物中的应用 - Google Patents
表儿茶素没食子酸酯在制备治疗高原脑水肿药物中的应用 Download PDFInfo
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Abstract
本发明涉及医药制备技术领域,公开了表儿茶素没食子酸酯制备治疗高原脑水肿药物中的应用,本发明的研究表明表儿茶素没食子酸酯对高原脑水肿有显著的治疗作用。表儿茶素没食子酸酯可以通过抑制小胶质细胞激活、降低水通道蛋白4的表达,改善低氧对血脑屏障的破坏,降低脑水含量。与现有技术相比,表儿茶素没食子酸酯作为治疗高原脑水肿药物或药物的活性成分,具有效果明显、使用方便、副作用低等优点。
Description
技术领域
本发明属于医药制备技术领域,尤其涉及表儿茶素没食子酸酯在制备治疗高原脑水肿药物中的应用。
背景技术
我国高原面积辽阔,占国土总面积26%,占世界医学高原面积74.4%,具有重要的经济价值、社会价值和军事价值。每年进入高原的流动人口超过2000万。平原人群急进高原因低氧低压、寒冷干燥等地理气候特点可引发机体组织器官的强烈不适,诱发急性高原病,严重者甚至引发高原脑水肿。高原脑水肿是高原疾病中较为罕见但病情极为凶险的一种高原病。临床上,高原脑水肿表现为严重的认知功能障碍、神经精神症状、共济失调、昏迷等,而预防或治疗高原脑水肿一直是高原病防治的难点。目前临床常用乙酰唑胺、地塞米松及非甾类抗炎药对乙酰氨基酚或阿司匹林等对症治疗,或使用氨茶碱、呋塞米治疗水肿,使用普拉洛尔治疗心率过快,使用螺内酯治疗钠潴留等。但上述药物,均有副作用大,效果差异大,针对性弱等缺点。
高原脑水肿的发生机制目前尚不完全清晰,但基本认为与血管通透性增强诱发的血管源性水肿及胶质细胞炎性反应引发的细胞毒性水肿有关。其中,小胶质细胞在血管炎性水肿及细胞毒性水肿中均起重要的调控作用。已知低氧可激活小胶质细胞,活化的小胶质细胞可向血管募集并通过吞噬作用破坏内皮紧密连接,造成血管通透性增加,诱发血管源性水肿;同时可释放促炎因子,诱发头痛,并引起星形胶质细胞水通道蛋白4(AQP4)的表达上升,增强星形胶质细胞的储水能力,造成脑内含水量增加,引发细胞毒性水肿。因此,靶向小胶质细胞的激活可有效治疗高原脑水肿。
表儿茶素没食子酸酯(ECG)为儿茶素家族中的一种,是具有生物氧化作用的多酚类化合物。其已知的类似物为表没食子儿茶素没食子酸酯(EGCG),其主要药效作用有:(1)降低血脂,抑制动脉粥样硬化。(2)增强毛细血管,降低血糖。(3)抗辐射。(4)防衰老。(5)抗癌抗突变。(6)杀菌作用。目前,关于EGCG调控小胶质细胞的炎症反应,用于治疗神经系统的相关疾病已见广泛报道,但有关ECG在神经系统疾病中的治疗还未见研究和报道。
发明内容
本发明的目的在于提供表儿茶素没食子酸酯(ECG)在制备治疗高原脑水肿药物中的应用。ECG可通过抑制小胶质细胞激活,显著抑制小胶质细胞向血管的募集,抑制水通道蛋白4(AQP4)的表达,从而抑制脑水含量的上升,对低压低氧诱发的高原脑水肿具有良好的治疗作用。
为解决上述技术问题,本发明提供了ECG在制备用于治疗高原脑水肿中的应用,所述ECG的分子式为C22H18O10,CAS号为1257-08-5,化学结构式如下式所示:
其中,所述高原脑水肿为高原低压低氧环境暴露导致的脑水含量增加或共济失调;
进一步的,所述高原脑水肿包括急性高原暴露或慢性高原暴露过程中诱发的脑水肿疾病;。
进一步的,所述治疗高原水肿为通过抑制小胶质细胞活化和/或降低水通道蛋白4的表达改善低氧对血脑屏障的破坏;
进一步的,所述ECG为单独使用或与其他药物联合使用;
进一步的,所述药物的剂型为颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、滴丸剂或注射剂。
在临床应用时,以常规的制剂工艺,单独使用ECG或与将ECG与其他药物配合制备成在临床上可以使用的颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、滴丸剂或注射剂。
进一步的,所述药物的给药方式为口服给药或注射给药。
与现有技术相比,本发明通过利用ECG抑制低压低氧处理后的小鼠脑区的小胶质细胞激活,可以显著减少小胶质细胞向血管的募集,降低AQP4的表达水平,降低脑含水量,对高原脑水肿有明显的治疗作用,具有见效快、效果明显、使用方便等优点。由于ECG为儿茶素类物质,已在临床广泛应用,故本发明的临床推广风险较低。
附图说明
图1为对照小鼠、低压低氧暴露小鼠、腹腔注射ECG并低压低氧暴露的小鼠大脑皮层含水量对比图;
图2为对照小鼠、低压低氧暴露小鼠、腹腔注射ECG并低压低氧暴露的小鼠大脑皮层中AQP4蛋白表达水平检测的免疫印迹图及其统计图;
图3为对照小鼠、低压低氧暴露小鼠、腹腔注射ECG并低压低氧暴露的小鼠海马CA1区活化的小胶质细胞免疫荧光标记图及其统计图;
图4为对照小鼠、低压低氧暴露小鼠、腹腔注射ECG并低压低氧暴露的小鼠活化的小胶质细胞向血管募集情况的免疫荧光标记图及其统计图。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
本发明所用的表儿茶素没食子酸酯(ECG)英文名为Epicatechin gallate,CAS号为:1257-08-5,分子式为:C22H18O10,分子量为:442.37,购于Selleck公司,产品货号为S3925。
本发明实施例所用试剂除另有注明,均可以从销售公司获得。
实施例1
ECG减轻低压低氧暴露诱导的高原脑水肿模型小鼠脑部水肿效果实验:
(1)对照组:4只25g雄性成年小鼠。
(2)HH组:4只25g雄性成年小鼠,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
(3)HH+ECG组:4只25g雄性成年小鼠,腹腔注射100mg/kg ECG 1小时后,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
上述实验结束后,迅速剥离小鼠大脑皮层,马弗炉中100℃烘干24小时。称取烘干前后的脑湿重与干重。脑水含量的计算公式:Brain Water Content(%)=(脑湿重-脑干重)/脑失重×100%。由图1可知,HH组脑含水量显著增加,符合高原脑水肿模型的特征。HH+ECG组中,脑含水量相对于HH组明显下降。因此,证明ECG可以有效改善HH诱导的脑水肿症状。
实施例2
ECG减轻低压低氧暴露诱导的高原脑水肿模型小鼠脑部AQP4蛋白表达实验:
(1)对照组:4只25g雄性成年小鼠。
(2)HH组:4只25g雄性成年小鼠,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
(3)HH+ECG组:3只25g雄性成年小鼠,腹腔注射100mg/kg ECG 1小时后,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
上述实验结束后,小鼠经心脏灌流去除全身血液。迅速剥离小鼠大脑皮层,组织匀浆后提取蛋白质。利用Western Blot法对皮层中AQP4蛋白进行显色,以内参蛋白β-Actin进行校准。最后,根据其灰度值计算AQP4蛋白的相对表达水平。由图2可知,HH组脑内AQP4表达水平显著上调,符合高原脑水肿模型的特征。HH+ECG组中,AQP4蛋白水平相对于HH组明显下降。因此,证明ECG可以有效改善高原脑水肿模型小鼠脑内AQP4蛋白表达上调。
实施例3
ECG减少低压低氧暴露诱导的高原脑水肿模型小鼠脑部活化的小胶质细胞数量:
(1)对照组:4只25g雄性成年小鼠。
(2)HH组:4只25g雄性成年小鼠,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
(3)HH+ECG组:4只25g雄性成年小鼠,腹腔注射100mg/kg ECG 1小时后,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
上述实验结束后,小鼠经心脏灌流去除全身血液并使用4%中性多聚甲醛固定。固定后脑组织进行冰冻切片,厚度40μm。利用免疫荧光法标记Iba1,以示踪活化的小胶质细胞。使用DAPI染料标记细胞核便于定位。使用激光共聚焦显微经对切片的CA1区进行定位并拍照。最后,对照片中阳性信号(绿色为Iba1)进行计数统计。由图3可知,HH组脑内活化小胶质细胞的数量显著增加,符合高原脑水肿模型的特征。HH+ECG组中,活化的小胶质细胞数量相对于HH组明显下降。因此,证明ECG可以有效改善高原脑水肿模型小鼠脑内小胶质细胞的过度激活。
实施例4
ECG减少低压低氧暴露诱导的高原脑水肿模型小鼠脑部,活化的小胶质细胞向血管募集的比例:
(1)对照组:4只25g雄性成年小鼠。
(2)HH组:4只25g雄性成年小鼠,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
(3)HH+ECG组:4只25g雄性成年小鼠,腹腔注射100mg/kg ECG 1小时后,在模拟海拔7000米高度的低压低氧舱中暴露48小时。
上述实验结束后,小鼠经心脏灌流去除全身血液并使用4%中性多聚甲醛固定。固定后脑组织进行冰冻切片,厚度40μm。利用免疫荧光法标记Iba1,以示踪活化的小胶质细胞;标记Lamnin以示踪血管。使用激光共聚焦显微经对切片进行拍照。最后,统计与laminin共标的Iba信号。由图4可知,HH组小鼠大脑中,向血管募集的小胶质细胞数量显著增加,符合高原脑水肿模型的特征。HH+ECG组中,向血管募集的小胶质细胞数量相对于HH组明显下降。因此,证明ECG可以有效改善高原脑水肿模型小鼠脑内小胶质细胞向血管募集。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想,而非对其限制。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明的保护范围内。
Claims (6)
1.表儿茶素没食子酸酯在制备治疗高原脑水肿药物中的应用,其特征在于,所述表儿茶素没食子酸酯的分子式为C22H18O10,化学结构式如下式所示:
其中,所述高原脑水肿为高原低压低氧环境暴露导致的脑水含量增加或共济失调。
2.根据权利要求1所述的应用,其特征在于,所述高原脑水肿包括急性高原暴露或慢性高原暴露过程中诱发的脑水肿疾病。
3.根据权利要求1所述的应用,其特征在于,所述治疗高原水肿的药物具体为通过抑制小胶质细胞活化和/或降低水通道蛋白4的表达改善低氧对血脑屏障的破坏的药物。
4.根据权利要求1~3任一项所述的应用,其特征在于,所述儿茶素没食子酸酯为单独使用或与其他药物联合使用。
5.根据权利要求1~3任一项所述的应用,其特征在于,所述药物的剂型为颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、滴丸剂或注射剂。
6.根据权利要求1~3任一项所述的应用,其特征在于,所述药物的给药方式为口服给药或注射给药。
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