CN116919930A - 萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用 - Google Patents
萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域，具体涉及一种萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用。萜类化合物调节脑膜淋巴引流，治疗神经退行性疾病的异常蛋白沉积中的应用。萜类化合物或其制剂可以以萜类化合物为单一有效组分或者与其他治疗药物协同应用。萜类化合物可以提高血管内皮生长因子表达，促进淋巴系统的生长，加快脑脊液流动，扩张淋巴管，增强淋巴引流。萜类化合物通过调节硬脑膜淋巴引流，增强了神经退行性疾病中异常蛋白沉积的清除，从而有效的提高了萜类化合物对神经退行性疾病的预防及治疗作用。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用。
背景技术：
萜类化合物指具有(C5H8)n通式以及其含氧和不同饱和程度的衍生物，根据其结构中异戊二烯单位的数目又分为单萜、倍半萜、二萜、三萜、四萜、多萜等；或者根据碳环的有无和数目分为链萜、单环萜、双环萜等。萜类化合物在自然界分布广泛，种类繁多，是各类天然物质中最多的一类化合物。现代药理研究表明，萜类化合物具有多种生物活性，如增强渗透、抗炎、抗菌、免疫调节、抗衰老、神经保护等作用。其中冰片、薄荷醇等具有醒脑开窍，清热止痛等功效可作为引药上行、开窍醒脑之良药。现代研究表明，萜类化合物调节淋巴系统，增加其他药物进入淋巴系统，提高淋巴引流作用。同时研究表明，萜类化合物可打开血脑屏障，促进其他药物穿过血脑屏障进入大脑发挥疗效。
神经退行性疾病是机体神经元结构和功能逐渐丧失导致认知和运动障碍的一类疾病，包括阿尔兹海默病(Alzheimer’s Disease,AD)，帕金森病(Parkinson’s Disease,PD)、肌萎缩侧索硬化症(Amyotrophic lateral sclerosis,ALS)。亨廷顿氏病(Huntington’s Disease,HD)及脊髓性肌萎缩症(spinal muscular atrophy，SMA)等。随着人口老龄化的加剧，神经退行性疾病的发病率逐年攀升，逐渐成为老龄化人口常见的死亡原因。AD和PD在我国的患病率分别为3.21％和1.7％，患者数分别超过800万和250万。随着对神经退行性疾病研究的不断深入，有关神经退行性疾病的发病因素主要包括蛋白错误折叠和聚集、氧化应激、炎症、线粒体功能障碍等，主要是通过抑制炎性反应，即降低肿瘤坏死因子α(tumor necrosis factor-αTNF-α)含量、抑制IL-6和IL-1β释放实现对神经退行性疾病的治疗。或者通过调节血脑屏障通透性、抑制神经细胞凋亡等机理发挥中枢神经系统保护的作用。由于目前尚没有有效的治疗手段延缓和阻止病情恶化，所以开发有效的神经退行性疾病治疗方法是当今世界难题。
几十年来，中枢神经系统一直被称为免疫特权器官，由于脑实质中没有淋巴系统，对于脑内的细胞碎片和毒性分子可能由跨血管途径、小胶质细胞吞噬作用及类淋巴途径清除。随着脑膜淋巴管的发现和表征促使人们重新评估中枢神经系统内废物清除途径。研究表明，脑膜淋巴管通过将大分子从中枢神经系统引流到颈部淋巴结，在维持脑稳态方面发挥着重要作用。脑膜淋巴循环已被证实与阿尔兹海默症、帕金森、脑水肿及脑肿瘤等多种脑部疾病相关。研究表明，通过调节硬脑膜淋巴循环，在阿尔兹海默症、帕金森、脑中风的疾病中发挥潜在的预防及治疗作用。
通过消融硬脑膜淋巴管或结扎颈部淋巴管可导致阿尔兹海默症模型小鼠脑内Aβ积累，加重认知障碍。进一步Aβ积聚可能会导致淋巴功能障碍，并产生降低Aβ清除率的正反馈回路。目前研究报道，使用血管内皮生长因子(VEGF-C)或者物理刺激可促进硬脑膜淋巴管新生及扩张，从而加快脑内异常蛋白淋巴途径清除，有效治疗神经退行性疾病。但是仍缺乏有效药物调节硬脑膜淋巴循环，进而需要进一步研究。
发明内容
本法民目的在于提供一种萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用。
为实现上述目的，本发明所采用的技术方案是：
一种萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用。
所述萜类化合物在调节脑膜淋巴引流抑制中枢神经系统的异常蛋白沉积中的应用。
所述萜类化合物为单萜、倍半萜类化合物以及前述化合物的衍生物中的一种或几种，或含有化合物和/或衍生物中的一种或几种的制剂。
所述萜类化合物为月桂烯、罗勒烯、香茅醇、香叶醇、橙花醇、香橙醛、芳樟醇、薰衣草醇、柠檬醛、香茅醛、万寿菊酮、柠烯、松油烯、水芹烯、薄荷醇、薄荷酮、松油醇、香芹醇、香芹酮、柠檬烯、紫苏醛、紫苏醇、胡薄荷醇、蒎烯、松香芹醇、桃金娘烯醇、马鞭草烯醇、樟脑、龙脑、冰片、茨烯、日菊醇、侧柏酮、芍药苷、长叶醛、金合欢烯、橙花叔醇、青蒿素、马桑毒素、香橙烯、马榄烯、石竹烯、蛇麻烯、柠檬烯、檀香醇、长叶烯、马兜铃烯、愈创木烯、桉油精中的一种或几种。
所述萜类化合物为月桂烯，香橙醛，柠檬醛、薄荷醇、薄荷酮，紫苏醛，紫苏醇、香芹酮，香芹醇、柠檬烯，冰片，龙脑中的一种或几种。
所述制剂为以所述化合物及其衍生物作为活性物质，其中，活性物质占制剂质量的0.01％-10％。
所述制剂为固体制剂、半固体制剂、液体制剂、微粒制粒中的一种或几种的组合。
所述中枢神经系统的异常蛋白沉积可由阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性脊髓侧索硬化症、脑损伤、脊髓小脑共济失调中的Aβ蛋白、Tau蛋白、α-突触核蛋白、亨廷顿蛋白的一种或几种引起。
所述萜类化合物或其制剂可以以萜类化合物为单一有效组分或者与其他治疗药物协同应用。
本发明具有以下优势：
本发明利用萜类化合物通过调节脑膜淋巴循环，提高淋巴引流，促进脑内异常蛋白通过淋巴途径清除，进而有效实现通过萜类化合物对中枢神经系统的异常蛋白沉积的神经退行性疾病的抑制作用；具体为：
(1)本发明特定萜类化合物可以促进脑内异常蛋白沉积清除至外周，进一步提高抑制神经退行性疾病。
(2)本发明特定萜类化合物具有高效的促进渗透作用，促进脑实质内异常蛋白沉积进入淋巴系统，调节脑膜淋巴引流，提高脑内异常蛋白淋巴引流效率。
(3)本发明特定萜类化合物具有通诸窍，抗炎、抗病毒、抗氧化、神经保护等作用，同时，由含特定萜类化合物制成微粒制剂，可改善萜类化合物生物利用度，进一步发挥神经退行性疾病的预防和治疗作用。
(4)本发明特定萜类化合物活性高，可以提高血管内皮生长因子表达，进而扩张淋巴管，提高淋巴引流，促进脑实质内异常蛋白进入淋巴系统。萜类化合物可增加脑脊液流动，进一步增强淋巴循环，提高了异常蛋白清除至外周的淋巴引流效率，萜类化合物毒性低，起效快，安全性高，可有效的预防和治疗神经退行性疾病。
附图说明
图1为本发明实施例提供的冰片纳米晶增加脑内FITC-OVA蛋白清除的小动物活体成像结果图。
图2A为本发明实施例提供的冰片纳米晶提高硬脑膜中淋巴管内皮细胞标志物Lyve-1和FITC-OVA蛋白共定位的免疫荧光成像图。
图2B为本发明实施例提供的冰片纳米晶提高颈深淋巴结中淋巴管内皮细胞标志物Lyve-1和FITC-OVA蛋白共定位的免疫荧光成像图。
图3A为本发明实施例提供的冰片纳米晶对硬脑膜淋巴管扩张效果图。
图3B为本发明实施例提供的冰片纳米晶提高硬脑膜内VEGF-C含量图。
图4A为本发明实施例提供的对照组和冰片纳米粒对脑内Aβ1-42寡聚体药代动力学及AUC结果图。
图4B为本发明实施例提供的对照组和冰片纳米粒组颈深淋巴结内Aβ1-42寡聚体药代动力学及AUC结果图。
图5A为本发明实施例提供的冰片纳米粒提高硬脑膜淋巴管内皮细胞标志物Lyve-1和FITC-Aβ1-42共定位免疫荧光成像结果图。
图5B为本发明实施例提供的冰片纳米粒提高颈深淋巴结中淋巴管内皮细胞标志物Lyve-1和FITC-Aβ1-42共定位免疫荧光成像结果图。
图6为本发明实施例提供的冰片胶束治疗AD药效结果图，图6A为训练期间各组小鼠潜伏期，图6B为各组小鼠行动轨迹图，图6C为各组小鼠穿越平台次数，图6D为各组小鼠在目标象限停留时间。
图7为本发明实施例提供的冰片胶束治疗PD药效结果图，图7A为各组小鼠旷场行为学结果图，图7B为各组小鼠爬杆行为学结果图，图7C为各组小鼠悬挂行为学结果图，图7D为各组小鼠转棒行为学结果图。
具体实施方式
下面结合具体实施例及说明书附图对本发明做进一步的详细描述，下述实施例以冰片为例，但本发明的实施方式不限于此。
本发明利用特定萜类化合物及其含特定萜类化合物的制剂调节脑膜淋巴引流抑制神经退行性疾病的异常蛋白沉积的应用。萜类化合物或其制剂可以以萜类化合物为单一有效组分或者与其他治疗药物协同应用。萜类化合物可以增加血管内皮细胞生长因子表达，促进淋巴管扩张，增加淋巴引流，促进了脑实质内蛋白进入淋巴管，同时加速脑脊液流动，加快颅内异常蛋白清除至外周，从而提高了萜类化合物对神经退行性疾病的预防和治疗作用。
实施例1冰片纳米胶束的制备
将冰片研磨过200目筛，分别精密称取5mg、10mg、25mg冰片，分别溶于丙二醇溶液中，超声溶解，加入适量PEG400和吐温-80，加入纯化水超声混匀，即得1mg/mL(0.1％)、2mg/mL(0.2％)、5mg/mL(0.5％)冰片纳米胶束。
实施例2冰片纳米晶的制备
分别精密称取0.5mg、25mg、50mg冰片，溶于1mL乙醇中，分别高速搅拌条件下，缓慢滴加4mL 1％甘油溶液中，500W探头超声10min，超声3s停3s，分别制成0.1mg/mL(0.01％)、5mg/mL(0.5％)、10mg/mL(1％)冰片纳米晶。
实施例3冰片纳米粒的制备
分别精密称取0.5mg、50mg、500mg冰片，分别加入20mg大豆磷脂S100加入圆底烧瓶中，加入5mL无水乙醇：丙酮混合溶液，超声至固体全部溶解，50℃搅拌2.5h。精密称取100mgHPMC加入适量水滴加至冰片磷脂混合溶液中，继续搅拌0.5h，50℃减压除去溶剂，得到干燥薄膜，加入5mL纯化水，500W探头超声(工作3s，停3s)，即得0.1mg/mL(0.01％)、10mg/mL(1％)、100mg/mL(10％)冰片纳米粒。
实施例4冰片纳米晶清除脑内异常蛋白
以FITC-OVA为模型蛋白。对照组和冰片组小鼠通过异氟烷麻醉，并将头部固定在立体定位架中，在皮肤上做一个切口暴露颅骨，并在前囟后0.6mm,旁开1.5mm，深1.7mm使用微量注射器进针，以0.2μL/min注射速率于脑实质内注射5μL FITC-OVA蛋白，注射完成后，注射器留在原位5min以防止回流，然后缝合头皮。冰片组静脉注射0.2mL的0.1mg/mL(0.01％)冰片纳米晶，对照组同等静脉注射0.2mL生理盐水，冰片组和对照组分别于注射后0.17、0.5、1、2h摘取脑。通过小动物活体成像观察各组脑及淋巴结内药物分布(参见图1)。由图1结果可知，随着时间的延长，冰片组脑内残留量显著减少，说明冰片可以加快脑内大分子的清除。
实施例5冰片调节脑膜淋巴循环清除脑内异常蛋白
以FITC-OVA为模型蛋白。对照组和冰片组小鼠通过异氟烷麻醉，并将头部固定在立体定位架中，在皮肤上做一个切口暴露颅骨，并在前囟后0.6mm,旁开1.5mm,深1.7mm使用微量注射器进针，以0.2μL/min注射速率于脑实质内注射5μL FITC-OVA蛋白，注射完成后，注射器留在原位5min以防止回流，然后缝合头皮。冰片组静脉注射0.2mL的5mg/mL(0.5％)冰片纳米晶，对照组同等静脉注射0.2mL生理盐水，冰片组和对照分别于注射后1h，各组小鼠心脏灌流，摘取小鼠硬脑膜和颈深淋巴结，通过免疫荧光技术标记淋巴管内皮细胞蛋白Lyve-1，进一步使用荧光成像，通过与FITC-OVA共定位表征冰片清除异常蛋白途径(参见图2)。
由图2(A)可知，硬脑膜中FITC-OVA可与Lyve-1蛋白共定位，说明蛋白通过硬脑膜淋巴途径清除，同时冰片组中硬脑膜淋巴管中FITC-OVA分布高于对照组，说明冰片能促进脑内异常蛋白进入淋巴系统。
在各组颈深淋巴结中发现，见图2(B)，冰片组FITC-OVA分布高于对照组，进一步说明冰片通过促进脑内异常蛋白进入硬脑膜淋巴系统外排至外周颈深淋巴管中清除。
实施例6冰片纳米晶提高VEGF-C蛋白表达增加硬脑膜淋巴管扩张
KM小鼠皮下注射10μL的10mg/mL(1％)冰片纳米晶，1h后心脏灌流，通过外科手术剥离硬脑膜，通过免疫染色观察淋巴管结构。对照组为皮下注射10μL的生理盐水。
结果如图3(A)所示，其中经冰片给药后实验组的小鼠淋巴管直径大于对照组，即经冰片给药后可扩张淋巴管，促进淋巴循环。同样冰片脚掌皮下注射后，使用pH 7.4PBS灌注，摘取剥离硬脑膜，采用Elisa试剂盒检测VEGF-C含量，实验方法同试剂盒使用说明，结果见图3(B)，冰片可提高硬脑膜内VEGF-C含量，是对照组的1.81倍，说明冰片通过调节VEGF-C，促进淋巴管扩张。
实施例7冰片纳米粒对Aβ1-42寡聚体的脑清除作用
Aβ1-42寡聚体制备：精密称取1mg Aβ1-42粉末加入220μL预冷的六氟异丙醇(HFIP)中，超声溶解，室温孵育60min；然后转移到通风橱内，挥干溶剂，加入44μL无水DMSO，制成5mM/L Aβ1-42合成肽，精密加入2152μLPBS缓冲溶液，得到50μM/L的Aβ1-42合成肽，于4℃下孵育24h，14000r/min离心10min，转移上清液至新管即为寡聚体。取12只小鼠，随机分为4组，每组3只，各组小鼠侧脑室注射5μL Aβ1-42寡聚体。冰片组采用实施例3中制备100mg/mL(10％)冰片纳米粒，分别以10mg/kg、20mg/kg、30mg/kg给药量作为低、中、高剂量组进行口服给药。对照组小鼠口服同等体积的生理盐水。各组分别于给药后0.17、0.5、1、4、8、12、24h取小鼠脑、淋巴结，使用Elisa试剂盒检测含量。由图4结果可知，不同浓度冰片均可减少脑内Aβ1-42寡聚体，分别减少41.03％、36.06％和23.02％。同时相比于对照组，中剂量和高剂量组冰片可以增加颈深淋巴结中Aβ1-42寡聚体含量。说明冰片可以促进脑内Aβ1-42蛋白通过淋巴途径被清除至外周。
实施例8冰片纳米粒通过淋巴途径清除脑内Aβ1-42寡聚体
小鼠通过异氟烷麻醉，并将头部固定在立体定位架中，在皮肤上做一个切口暴露颅骨，并在前囟后0.6mm，旁开1.5mm，深1.7mm使用微量注射器进针，以0.2μL/min注射速率于脑实质内注射5μL FITC-Aβ1-42蛋白，注射完成后，注射器留在原位5min以防止回流，然后缝合头皮。冰片组静脉注射0.2mL的10mg/mL(1％)冰片纳米粒，对照组同等静脉注射0.2mL生理盐水，冰片组和对照组分别于注射后1h，小鼠心脏灌流，摘取小鼠硬脑膜和颈深淋巴结，通过免疫荧光技术标记淋巴管内皮细胞蛋白Lyve-1，进一步使用荧光成像，通过与FITC-Aβ1-42共定位表征冰片清除异常蛋白途径。
结果见图5，硬脑膜中FITC-Aβ1-42可与Lyve-1蛋白共定位，说明蛋白通过硬脑膜淋巴途径清除，同时冰片组中硬脑膜淋巴管中FITC-Aβ1-42分布高于对照组，说明冰片能促进脑内异常蛋白进入淋巴系统。说明冰片也可以促进脑内Aβ1-42蛋白进入硬脑膜淋巴系统并清除至外周颈深淋巴结。
实施例9冰片胶束对AD药效作用
将小鼠随机分为对照组、模型组、冰片预防组和治疗组。造模组和治疗组小鼠异氟烷麻醉，碘伏擦拭头部皮肤并剪开，暴露前囟点，海马体位置为前囟点后2mm，旁开1.5mm，深2mm处，使用微量注射器精密分别精密吸取3μL Aβ1-42注射至双侧海马体中，控制注射速度在1-2μL/min，注射完成后，原位停留3min后拔出注射器，避免药物渗出，使用手术尼龙线缝合头皮，擦拭碘伏，放于加热垫恢复苏醒。于造模3天后，冰片治疗组小鼠按照20mg/kg给药剂量每天口服给予2mg/mL(0.2％)冰片纳米胶束，冰片预防组小鼠按照20mg/kg给药剂量于造模前10天，每日1次灌胃给予20mg/kg的2mg/mL(0.2％)冰片纳米胶束，对照组和模型组小鼠口服等量的生理盐水。
于造模7天后进行水迷宫测试，测试前至少30min将小鼠送到待检测实验室适应环境。水迷宫测试包括4天训练期、1天检测期。训练过程中，小鼠每天进行4次试验。连续4天，在1.2m的水池中找到一个直径为10cm的隐藏平台，该平台位于水面以下1cm处。水温保持在22℃左右。水池四等分分别记为四象限，分别在四象限安置不同形状标志物作为视觉提示，帮助水下平台的空间导航和定位。记录小鼠平台的潜伏期，即小鼠找到并爬上平台所需的时间，最长为60s。允许每只小鼠在平台上停留30s，然后将其从水迷宫中放回笼中。如果小鼠60s内未找到平台，则手动将其引导至平台上，并在30s后放回原笼中。每只小鼠实验间隔至少为5min。每天分别进行4个方向入水口的训练。在第5天，将平台从水迷宫中移除，并对每只小鼠进行60s的检测试验。所有水迷宫测试均在开灯阶段的下午3点至8点之间进行。在训练和检测过程中，使用自动跟踪系统记录数据，计算训练期中四个试验每天的平均潜伏期(s)。检测试验计算平台象限中的时间、平台穿越次数及行动轨迹。
由图6A可见，为各组小鼠逃避潜伏期，对照组、冰片预防组和治疗组小鼠潜伏期随训练时间延长均低于模型组小组。图6B为各组小鼠游泳轨迹图。图6C结果可见冰片预防组和治疗组小鼠平台穿越次数显著高于模型组，说明冰片可改善造模小鼠的认知记忆。图6D为小鼠在平台所在区域的探索时间，由结果可知预防组和治疗组小鼠在目标象限停留时间高于模型组。综上说明冰片可改善造模小鼠的记忆障碍，对AD有一定的预防和治疗作用。
实施例10冰片胶束对PD药效作用
小鼠于造模前进行旷场、爬杆、悬挂、转棒疲劳行为学训练，根据行为学能力，筛选小鼠入组。小鼠随机分为4组，分别为对照组、模型组、冰片预防组、冰片治疗组。模型组和冰片预防组及冰片治疗组小鼠按照30mg/kg腹腔注射1-甲基-4-苯基-1,2,3.6-四氢吡啶(1-methyl-4-pheny-1,2,3,6-tetrahy-dropyridine,MPTP)，每日1次，连续注射7天。对照组同等注射等量的生理盐水。冰片治疗组小鼠于造模结束后按照20mg/kg给药剂量口服给予20mg/kg的2mg/mL(0.2％)冰片纳米胶束，冰片预防组小鼠于造模前10天，按照20mg/kg给药剂量每日1次灌胃给予2mg/mL(0.2％)冰片纳米胶束，对照组和模型组小鼠灌胃等量的生理盐水，每日1次，给药后第7d检测各组行为学效果。
旷场实验：所用实验箱为尺寸：250×250×300mm旷场，周壁的颜色为黑色，底面为白色。正上方架摄像头，视野覆盖整个旷场。将动物放置在正中央，同时进行摄像和计时，时间为5min。通过计算机示踪分析系统来分析动物在一定时间内的活动状态。
爬杆实验：将一直径为2.5cm的塑料球固定于长50cm、粗1.5cm的亚克力杆顶端,缠上纱布以防打滑，底部固定于大小合适纸箱底部,然后将被测小鼠置于球上,记录由球上爬至杆子底部所需时间。
评分标准为:3分,爬杆时间＜3.0s；2分,爬杆时间为3.01～6.0s；1分,爬杆时间为6.01～12.0s；0分,爬杆时间＞12.00s。重复测定3次，每次间隔3min。
悬挂实验：将被测小鼠两前爪置于30cm长,25cm高水平线中点，细线离地面80cm左右，下方放置合适大小纸箱进行承接，而后放开小鼠，记录其落地前的时间。评分标准为:0-10s-0分，10-20s-1分，20-30s-2分，30-40s-3分，40-60s-4分，60-90s-5分，超过90s-6分。
转棒实验：将小鼠置于直径为3cm的旋转杆上，转速调整为30r/min，每次同时测定6只小鼠，每个隔室中1只。记录5分钟内，小鼠从转棒开始转动至掉落转棒所经历的时间。
可参考评分标准为:0-10s-0分，10-30s-1分，30-50s-2分，50-70s-3分，70-90s-4分，90-120s-5分，超过120s-6分。
结果由图7所示，图7A为各组小鼠旷场检测总路程，给药7天后，冰片预防组和治疗组小鼠总路程高于模型组。图7B为各组小鼠爬杆能力，相比于模型组小鼠，冰片预防组和治疗组小鼠爬杆时间较短，优于模型组。由图7C可知，给予冰片后，造模小鼠悬挂能力增强。由图7D可见，冰片可提高造模小鼠转棒停留时间，综上说明，冰片能显著改善帕金森造模小鼠的行为学能力，说明冰片具有预防和治疗PD的功效。
综上所述本发明采用萜类化合物相关制剂可清除脑内异常蛋白沉积，可以调节脑膜淋巴引流，扩张淋巴管，增加脑脊液引流，提高了脑内异常蛋白的清除，从而提高了神经退行性疾病的治疗作用。目前基于异常蛋白清除途径主要包括跨细胞途径转运、吞噬作用以及通过血管旁(淋巴)途径。且目前临床有关脑内异常蛋白清除的治疗效果并不令人满意，可能导致严重的副作用，如脑炎和脑膜炎等。所以调节脑膜淋巴功能代表一种新的预防性治疗策略，不仅可以延迟蛋白沉积导致疾病的发生和进展，还可以用于对抗因蛋白沉积而加剧的神经退行性疾病的治疗。
以上所述实施例仅为本发明较为佳的实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明技术范围内做出的变形及改进，都应包含在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求为准。
Claims (9)
1.一种萜类化合物在调节脑膜淋巴循环促进脑内异常蛋白通过淋巴途径清除中的应用。
2.按权利要求1所述的应用，其特征在于：所述萜类化合物在调节脑膜淋巴引流抑制中枢神经系统的异常蛋白沉积中的应用。
3.按权利要求1或2所述的应用，其特征在于：所述萜类化合物为单萜、倍半萜类化合物以及前述化合物的衍生物中的一种或几种，或含有化合物和/或衍生物中的一种或几种的制剂。
4.按权利要求3所述的应用，其特征在于，所述萜类化合物为月桂烯、罗勒烯、香茅醇、香叶醇、橙花醇、香橙醛、芳樟醇、薰衣草醇、柠檬醛、香茅醛、万寿菊酮、柠烯、松油烯、水芹烯、薄荷醇、薄荷酮、松油醇、香芹醇、香芹酮、柠檬烯、紫苏醛、紫苏醇、胡薄荷醇、蒎烯、松香芹醇、桃金娘烯醇、马鞭草烯醇、樟脑、龙脑、冰片、茨烯、日菊醇、侧柏酮、芍药苷、长叶醛、金合欢烯、橙花叔醇、青蒿素、马桑毒素、香橙烯、马榄烯、石竹烯、蛇麻烯、柠檬烯、檀香醇、长叶烯、马兜铃烯、愈创木烯、桉油精中的一种或几种。
5.按权利要求4所述的应用，其特征在于：所述萜类化合物为月桂烯，香橙醛，柠檬醛、薄荷醇、薄荷酮，紫苏醛，紫苏醇、香芹酮，香芹醇、柠檬烯，冰片，龙脑中的一种或几种。
6.按权利要求3所述的应用，其特征在于，所述制剂为以所述化合物及其衍生物作为活性物质，其中，活性物质占制剂质量的0.01％-10％。
7.按权利要求6所述的应用，其特征在于，所述制剂为固体制剂、半固体制剂、液体制剂、微粒制粒中的一种或几种的组合。
8.按权利要求1或2所述的应用，其特征在于：所述抑制中枢神经系统的异常蛋白沉积为可由阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性脊髓侧索硬化症、脑损伤、脊髓小脑共济失调中的Aβ蛋白、Tau蛋白、α-突触核蛋白、亨廷顿蛋白的一种或几种引起的中枢神经系统的异常蛋白沉积。
9.按权利要求1或2所述的应用，其特征在于：所述萜类化合物或其制剂可以以萜类化合物为单一有效组分或者与其他治疗药物协同应用。
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