CN101254185B - 环烯醚萜类化合物在制备促进神经细胞增殖和分化药物中的用途 - Google Patents
环烯醚萜类化合物在制备促进神经细胞增殖和分化药物中的用途 Download PDFInfo
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Abstract
本发明公开了环烯醚萜类化合物在制备促进神经细胞增殖和/或分化的药物中的用途以及用其治疗与神经细胞增殖和/或分化相关疾病的方法。
Description
技术领域
本发明涉及环烯醚萜类化合物在制备促进神经细胞增殖和/或分化的药物中的用途以及所制备的药物组合物。本发明也涉及用所述化合物或药物组合物治疗或预防与促进神经细胞增殖和/或分化有关的疾病或病症的方法。
技术背景
神经干细胞(neural stem cell,NSC)是指中枢神经***中具有自我更新能力并且能够分化产生成熟脑细胞(包括神经元、星形胶质细胞和少突胶质细胞)的多潜能细胞。神经干细胞具有自我更新能力、高增殖潜能以及多分化潜能,可分化成神经元、少突胶质细胞和星形胶质细胞等,神经干细胞产生的子代细胞对中枢神经***的发育、维持以及实施细胞替代治疗具有重要作用。NSC的发现和体外培养成功,为中枢神经***病的细胞替代疗法拓宽了道路。如治疗神经***退行性疾病,如帕金森病(PD)、阿尔茨海默病(AD)和亨廷顿病(HD),可以明显改善症状。同时,大量体外和在体实验已经证实成年脑中确实存在NSC,只是发育成熟后丧失了活性因子的刺激作用。这些细胞在一定的条件下,如脑组织损伤、缺血、生长因子刺激等,可以进行增殖、迁移和分化,新生的神经元可替代丢失的神经细胞发挥一定的功能。因此,研究有效的促进神经干细胞增殖和/或分化的方法有重要的意义。
环烯醚萜类化合物(Iridoids)是一类特殊的单萜化合物,其母核都为环状,具有烯键和醚键。1925年由伊蚁的防卫分泌物中首次分得伊蚁内酯,1958年O.Halpern和H.Schmid对plumieride结构的研究确定了环烯醚萜的基本骨架。植物界中的环烯醚萜类化合物是由焦磷酸香叶酯(GPP)经生物合成途径生成臭蚁二醛(iridodial),再缩醛衍生而成的,其基本骨架如下面结构式。
1.环烯醚萜的基本骨架
环烯醚萜分子中,C1-OH很活泼,易与糖结合,天然存在的环烯醚萜多为苷,且多为D-葡萄糖苷。包含但不仅有:
(1)普通环烯醚萜苷:①C-8环烯醚萜苷。②C-9环烯醚萜苷(第9个C接在C-4上)。③C-9环烯醚萜苷(第9个C接在C-8上)。④C-10环烯醚萜苷。如6’-乙酰车叶草苷、莫诺苷、马钱素、栀子苷、梓醇、黄蝉花素、黄蝉花定、车叶草苷、桃叶珊瑚苷、梓苷、去氧番木鳖苷、京尼平、鸡蛋花素、马鞭草苷、金吉苷。
(2)裂环环烯醚萜苷:如龙胆苦苷、龙胆苦酯苷,开联番木鳖苷、獐芽莱苦素等。
(3)Valeriana型环烯醚萜,如7,10,2’-3乙酰败酱甙、和10-乙酰败酱甙。
(4)Plumeria型环烯醚萜:如枸桔苷A。
(5)3,10位间形成氧桥的环烯醚萜,如3,10位间形成氧桥的环烯醚萜苷新月苷B。
(6)荆芥内酯相关类型环烯醚萜,有紫苷。
(7)变形的类环烯醚萜,例如新月苷A,B、8位有三元氧螺环结构的枸桔苷B。
(8)由几个环烯醚萜直接经酯键或由萜类、酚类连接而成。如缬草醚酯、去乙酰车叶草苷酸甲酯等。
本发明发明人通过对马钱素和莫诺苷的研究,发现环烯醚萜类对神经干细胞有良好的促增殖和/或促分化作用,因而完成了本发明。
发明内容
本发明一方面提供了环烯醚萜类化合物例如马钱素和/或莫诺苷在制备促进神经干细胞增殖和/或分化的药物中的用途。本发明另一方面也提供了含有环烯醚萜类化合物的药物组合物以及用所述化合物或组合物治疗与神经细胞增殖和/或分化有关疾病的方法。
随着现代分子生物学的迅速更新进步,人类将有可能研制出对已经发育完善的成体神经细胞的增殖与分化技术。基于环烯醚萜类化合物对神经干细胞的促增殖与分化作用,环烯醚萜类化合物对成体神经细胞也可能有促增殖与分化作用,进而治疗各种原因导致的以神经元缺失为特征的神经***疾病。
环烯醚萜类化合物的以上所述方法和用途可以是单独应用促使神经疾病患者神经***内尚存的干细胞增殖和分化,或者是对外源性干细胞移植到神经疾病患者神经***内进行增殖和分化达到治疗或预防神经***疾病目的。
本发明所述莫诺苷、马钱素,均具有环烯醚萜的基本骨架,可以从山茱萸按照已知方法提取,或从市售中得到。
马钱素(loganin) 莫诺苷(morroniside)
本发明的化合物也可按照本领域技术人员已知的方法加以合成。
本发明除了上列化合物以外,还打算涵盖这类化合物的同系物和类似物。在这种情况下,同系物是具有上述化合物的实质性结构相似性的分子,类似物是具有与结构相似性无关的实质性生物相似性的分子。
本发明还涵盖药物组合物,所述组合物包括环烯醚萜类化合物与有机和无机酸的药学上可接受的盐,例如酸加成盐,酸例如可以是盐酸、硫酸、甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸、磷酸等。药学上可接受的盐还可以借助无机碱和有机碱的处理而制备,无机碱例如钠、钾、铵、钙或铁的氢氧化物,有机碱例如异丙胺、三甲胺、2-乙氨基乙醇、组氨酸、普鲁卡因等。
本发明还涵盖药物组合物,所述组合物包括环烯醚萜类化合物的水合物。术语“水合物”包括但不限于半水合物、一水合物、二水合物、三水合物等。
本发明还涵盖药物组合物,所述组合物包括环烯醚萜类化合物的任意固体或液体物理形式。例如,环烯醚萜类化合物可以是结晶形式、无定形,并且具有任意的粒径。环烯醚萜类化合物粒子可以被微粉化,或者可以是聚结的微粒状颗粒、粉末、油、油悬液或任意其他固体或液体物理形式。
药物组合物
本发明化合物及其衍生物、片段、类似物、同系物、药学上可接受的盐或水合物可以与药学上可接受的载体或赋形剂一起制成适合于口服给药的药物组合物。这类组合物通常包含治疗有效量的任意上述化合物和药学上可接受的载体。优选地,有效量是有效地促进神经细胞增殖和/或分化的量并且小于导致患者毒性的量。
在本发明制剂中可以使用任意普遍用作载体或稀释剂的惰性赋形剂,例如树胶、淀粉、糖、纤维素材料、丙烯酸酯或其混合物。优选的稀释剂是微晶纤维素。组合物可以进一步包含崩解剂(例如交联羧甲基纤维素钠)和润滑剂(例如硬脂酸镁),另外可以包含一种或多种添加剂,选自粘合剂、缓冲剂、蛋白酶抑制剂、表面活性剂、增溶剂、增塑剂、乳化剂、稳定剂、粘度增加剂、甜味剂、成膜剂或其任意组合。此外,本发明组合物可以是控释制剂或即时释放制剂的形式。
一种实施方式是口服给药用药物组合物,包含环烯醚萜类化合物或其药学上可接受的盐或水合物、微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁。另一种实施方式包含50-70重量%的环烯醚萜类化合物或其药学上可接受的盐或水合物、20-40重量%的微晶纤维素、5-15重量%的交联羧甲基纤维素钠和0.1-5重量%的硬脂酸镁。另一种实施方式包含约50-200mg的环烯醚萜类化合物。
在一种实施方式中,药物组合物是口服给药的,因而被配制成适合于口服给药的形式,也就是固体或液体制备物。适合的固体口服制剂包括片剂、胶囊剂、丸剂、颗粒剂、小丸等。适合的液体口服制剂包括溶液、悬液、分散体、乳剂、油剂等。在一种本发明实施方式中,组合物被配制成胶囊剂。按照这种实施方式,本发明组合物除了环烯醚萜类化合物活性化合物和惰性载体或稀释剂以外,还包含硬明胶胶囊。
本文所用的“药学上可接受的载体”打算包括任意和所有的溶剂、分散介质、包衣、抗细菌与抗真菌剂、等渗剂和吸收延迟剂等,它们与药学给药是可相容的,例如无菌无热原的水。适合的载体描述在最新版Remington′s Pharmaceutical Sciences中,它是本领域的标准参考书,结合在此作为参考。这类载体或稀释剂的优选实例包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和5%人血清白蛋白。还可以使用脂质体和非水性载体,例如固定油。这类介质和试剂应用于药学活性物质是本领域熟知的。除非任何常规介质或试剂与活性化合物是不可相容的,其在组合物中的用途都涵盖在内。还可以向组合物掺入补充性活性化合物。
固体载体/稀释剂包括但不限于树胶、淀粉(例如玉米淀粉、预胶凝淀粉)、糖(例如乳糖、甘露糖醇、蔗糖、葡萄糖)、纤维素材料(例如微晶纤维素)、丙烯酸酯(例如聚甲基丙烯酸酯)、碳酸钙、氧化镁、滑石或其混合物。
就液体制剂而言,药学上可接受的载体可以是水性或非水性溶液、悬液、乳剂或油。非水性溶剂的实例有丙二醇、聚乙二醇和可注射的有机酯,例如油酸乙酯。水性载体包括水、醇/水溶液、乳液或悬液,包括盐水和经过缓冲的介质。油的实例有石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、橄榄油、葵花油和鱼肝油。溶液或悬液还可以包括下列组分:无菌稀释剂,例如注射用水、盐水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;和调节张性的试剂,例如氯化钠或葡萄糖。pH可以用酸或碱来调节,例如盐酸或氢氧化钠。
另外,组合物可以进一步包含粘合剂(例如***胶、玉米淀粉、明胶、卡波姆、乙基纤维素、瓜尔胶、羟丙基纤维素、羟丙基甲基纤维素、聚维酮)、崩解剂(例如玉米淀粉、马铃薯淀粉、藻酸、二氧化硅、交联羧甲基纤维素钠、交联聚维酮、瓜尔胶、淀粉羟乙酸钠、Primogel)、不同pH和离子强度的缓冲剂(例如Tris-HCl、乙酸盐、磷酸盐)、防止表面吸收的添加剂(例如白蛋白或明胶)、洗涤剂(例如吐温20、吐温80、Pluronic F68、胆汁酸盐)、蛋白酶抑制剂、表面活性剂(例如月桂基硫酸钠)、渗透增强剂、增溶剂(例如甘油、聚乙烯甘油)、助流剂(例如胶体二氧化硅)、抗氧化剂(例如抗坏血酸、偏亚硫酸氢钠、丁基化羟基茴香醚)、稳定剂(例如羟丙基纤维素、羟丙基甲基纤维素)、增粘剂(例如卡波姆、胶体二氧化硅、乙基纤维素、瓜尔胶)、甜味剂(例如蔗糖、阿斯巴甜、柠檬酸)、矫味剂(例如薄荷、水杨酸甲酯或橙味调料)、防腐剂(例如硫汞撒、苯甲醇、对羟基苯甲酸酯)、润滑剂(例如硬脂酸、硬脂酸镁、聚乙二醇、月桂基硫酸钠)、流动助剂(例如胶体二氧化硅)、增塑剂(例如邻苯二甲酸二乙酯、柠檬酸三乙酯)、乳化剂(例如卡波姆、羟丙基纤维素、月桂基硫酸钠)、聚合物包衣(例如泊洛沙姆或poloxamine)、包衣与成膜剂(例如乙基纤维素、丙烯酸酯、聚甲基丙烯酸酯)和/或助剂。
在一种实施方式中,与活性化合物一起配制的载体将保护化合物防止从机体迅速消除,例如控释制剂,包括植入物和微囊包封的递送***。可以使用生物可降解的、生物可相容的聚合物,例如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。这类制剂的制备方法对本领域技术人员而言将是显而易见的。材料还可以在商业上从Alza Corporation和Nova Pharmaceuticals,Inc获得。还可以使用脂质体悬液(包括定向于感染细胞的脂质体和病毒抗原的单克隆抗体)作为药学上可接受的载体。这些可以按照本领域技术人员已知的方法加以制备,例如美国专利No.4,522,811所述。
配制剂量单元形式的口服组合物尤其有利于轻松给药和剂量一致性。本文所用的剂量单元形式表示物理上离散的单元,适合作为受治疗者的单位剂量;每一单元含有与所需药物载体缔合的预定量活性化合物,根据计算产生所需的治疗效果。本发明剂量单元形式的规格取决于并且直接依赖于活性化合物的独特特征和所要达到的特定治疗效果,以及本领域围绕这样一种活性化合物就个体治疗而言所固有的限制。
药物组合物可以与给药指导一起包括在容器、包装或配药器中。
本发明化合物或组合物可以连续地重复每日给药达数天至数年。口服治疗可以持续一周至患者寿命。优选地,给药达连续五天,然后可以评价患者以确定是否需要进一步的给药。给药可以是连续的或间歇的,也就是连续几天治疗继之以休息期。
含有活性成分的药物组合物的制备是本领域熟知的,例如混合、造粒或压片过程。经常将活性治疗成分与药学上可接受的并且可与活性成分相容的赋形剂混合。就口服给药而言,将活性试剂与惯用于此目的的添加剂混合,例如载体、稳定剂或惰性稀释剂,再借助惯用方法转化为适合于给药的剂型,例如片剂、包衣片、硬或软明胶胶囊剂、水、醇或油溶液等,如上所述。
本发明化合物口服给药的总每日剂量在25至4000mg/m2之间,例如约25至1000mg、50-1000mg、100mg、200mg、300mg、400mg、600mg、800mg、1000mg等。通常,当对患者给药至多400mg时,将化合物作为单一剂量给药。就更高的总剂量而言(也就是大于400mg),将总量分为多个剂量,例如每日两次、每日三次等,优选地在当天内间隔相等的时间。例如,可以间隔12小时给以两剂,例如各500mg,一天的总剂量达到1000mg。
在一种当前优选的实施方式中,环烯醚萜类化合物对患者给药的每日总剂量为200mg。在另一种当前优选的实施方式中,环烯醚萜类化合物对患者给药的每日总剂量为400mg。在另一种当前优选的实施方式中,环烯醚萜类化合物对患者给药的每日总剂量为600mg。
化合物对患者给药的量小于将对患者导致毒性的量。在某些实施方式中,化合物对患者给药的量小于导致化合物在患者血浆中的浓度等于或超过化合物毒性水平的量。优选地,化合物在患者血浆中的浓度维持在约10nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约25nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约50nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约100nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约500nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约1000nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约2500nM。在另一种实施方式中,化合物在患者血浆中的浓度维持在约5000nM。在本发明的实施中,化合物应当对患者给药的最佳量将依赖于所使用的特定化合物和所治疗病症的类型。
在当前优选的本发明实施方式中,药物组合物包含普通环烯醚萜苷;微晶纤维素作为载体或稀释剂;交联羧甲基纤维素钠作为崩解剂;和硬脂酸镁作为润滑剂。在特别优选的实施方式中,环烯醚萜类化合物是莫诺苷或马钱素。
活性成分与各种赋形剂在制剂中的百分比可以各不相同。例如,组合物可以包含20至90重量%、优选50-70重量%的普通环烯醚萜苷。此外,组合物可以包含10至70重量%、优选20-40重量%的微晶纤维素作为载体或稀释剂。此外,组合物可以包含1至30重量%、优选5-15重量%的交联羧甲基纤维素钠作为崩解剂。此外,组合物可以包含0.1-5重量%的硬脂酸镁作为润滑剂。在另一种优选的实施方式中,组合物包含约50-200mg的环烯醚萜类化合物(例如50mg、100mg和200mg的环烯醚萜类化合物)。在特别优选的实施方式中,组合物是片剂或明胶胶囊剂的形式。
当前优选的本发明实施方式是环烯醚萜类化合物与微晶纤维素NF(Avicel Ph 101)、交联羧甲基纤维素钠NF(AC-Di-Sol)和硬脂酸镁NF的固体制剂,包含在明胶胶囊中。进一步优选的实施方式是200mg固体SAHA与89.5mg微晶纤维素、9mg交联羧甲基纤维素钠和1.5mg硬脂酸镁,包含在明胶胶囊中。
本发明药物组合物不仅可用于促进神经细胞的增殖和分化,而且对本领域技术人员而言应当显而易见的是,这些组合物可用于治疗多种已经发现环烯醚萜类化合物有用的疾病。
例如,已经发现环烯醚萜类化合物,可用于治疗各种原因导致的出现神经元缺失的疾病,包括中枢神经损伤,包含但不仅于缺血性、外伤性、以及酒精性脑或脊髓损伤;影响神经***的***性萎缩病、基底节退行性疾病、肌张力障碍、原发性的锥体外系疾病;以及神经***变性疾病。缺血性损伤,包括脑缺血(例如作为创伤、癫痫、出血或中风结果的脑损伤,它们均可以引起神经变性);肌萎缩性侧索硬化(ALS);多发性硬化;肌病,例如肌肉蛋白代谢病。
例如,已经发现环烯醚萜类化合物可用于治疗多种神经变性疾病,其非穷举性列表有:
I.以没有其他突出的神经病学病征存在的进行性痴呆为特征的障碍,例如阿尔茨海默氏病;阿尔茨海默型老年痴呆;和皮克氏病(脑叶萎缩)。
II.合并有进行性痴呆与其他突出的神经病学异常的综合征,例如A)主要见于成人的综合征(例如亨廷顿氏病、合并有痴呆与共济失调的多***萎缩和/或帕金森氏病的表现、进行性核上性麻痹(Steel-Richardson-Olszewski)、扩散性利维小体病和corticodentatonigral变性);和B)主要见于儿童或青年的综合征(例如哈-斯二氏病和进行性家族性肌阵挛性癫痫)。
III.***与运动渐进性异常的综合征,例如震颤麻痹(帕金森氏病)、striatonigral变性、进行性核上性麻痹、扭转张力障碍(扭转痉挛;变形性肌张力障碍)、痉挛性斜颈与其他运动障碍、家族性震颤和图雷特氏综合征。
IV.进行性共济失调的综合征,例如小脑变性(例如小脑皮质变性和橄榄体脑桥小脑萎缩(OPCA))和脊髓小脑变性(弗里德希氏共济失调和相关障碍)。
V.中枢自主神经***衰竭的综合征(Shy-Drager综合征)。
VI.没有感觉改变的肌肉虚弱和消瘦的综合征(运动神经元疾病,例如肌萎缩性侧索硬化、脊柱肌肉萎缩(例如婴儿脊柱肌肉萎缩(Werdnig-Hoffman)、青少年脊柱肌肉萎缩(Wohlfart-Kugelberg-Welander)和其他形式的家族性脊柱肌肉萎缩)、原发性侧索硬化和遗传性痉挛性截瘫。
VII.合并有肌肉虚弱和消瘦与感觉改变的综合征(进行性神经肌肉萎缩;慢性家族性多神经病),例如A.腓肌肉萎缩(Charcot-Marie-Tooth),B.肥大性间质性多神经病(Dejerine-Sottas),和C.各种形式的慢性进行性神经病。
VIII.进行性视觉丧失的综合征,例如色素性视网膜变性(色素性视网膜炎)和遗传性视神经萎缩(利伯氏病)。
下列实验细节部分中的实施例进一步阐述本发明。该部分有助于理解发明,但是不打算、也不应当被解释为以任何方式限制如下权利要求书所限定的发明。
附图说明:
图1.环烯醚萜类化合物马钱素和莫诺苷对神经干细胞增殖的影响。
A.对照组:用不加生长因子的DMEM/F12培养液培养6天,绝大部分细胞死亡(×200);B.不加生长因子的DMEM/F12培养液中添加马钱素50μg/ml,培养6天,神经干细胞球体积增大(×200);C.不加生长因子的DMEM/F12培养液中加入马钱素25μg/ml,培养14天,神经干细胞体积进一步增大(×200);D.不加生长因子的DMEM/F12培养液中添加莫诺苷25μg/ml,培养6天,可见神经干细胞球体积增大(×200);E.不加生长因子的DMEM/F12培养液中添加莫诺苷25μg/ml,培养14天,神经干细胞体积进一步增大(×200)。
图2.环烯醚萜类化合物马钱素和莫诺苷促进神经干细胞分化作用。
A对照组:用含1%胎牛血清(FBS)的DMEM/F12培养液诱导神经干细胞分化7天,单细胞从细胞球周缘迁出,迁出细胞的形态大致可分为两种:①小部分细胞胞体形态接近椭圆形,有2~3个细长的突起,类似于神经元的形态;②大部分细胞的形状不规则,突起较多,经免疫细胞化学实验结果分析,分别是神经元、胶质细胞和星形胶质细胞(×200)。B用含马钱素50ug/ml的DMEM/F12培养液(无FBS)诱导分化7天,细胞球几乎完全贴壁,分化较好,迁出的细胞非均匀的辐射状排列,而是细胞之间互相连接成网状(×200)。C用含莫诺苷50ug/ml的DMEM/F12培养液(无FBS)诱导分化7天,细胞球几乎完全贴壁,分化较好,迁出的细胞的突起首尾相连成“串珠状”(×200)。
图3.环烯醚萜类药物组合物促进脑损伤后神经干细胞增殖作用。
A正常大鼠海马齿状回有散在分布的Brdu阳性神经干细胞,阳性细胞胞核着色,多数呈卵圆形;B正常大鼠脑室下层有散在分布的Brdu阳性神经干细胞,阳性细胞胞核着色,多数呈卵圆形;C.脑缺血模型组大鼠海马齿状回的Brdu阳性神经干细胞较正常组显著增加;D.脑缺血模型组大鼠脑室下层的Brdu阳性神经干细胞较正常组显著增加;E给环烯醚萜类药物组合物(马钱素:莫诺苷组合物=1:1)后的脑缺血模型组大鼠海马齿状回Brdu阳性神经干细胞数目较正常组和模型组显著增加;F给环烯醚萜类药物组合物(马钱素:莫诺苷组合物=1:1)后的脑缺血模型组大鼠室管膜Brdu阳性神经干细胞数目较正常组和模型组显著增加。
实施例1
马钱素和莫诺苷促进神经干细胞存活增殖作用
一、实验目的
观察马钱素和莫诺苷对神经干细胞存活增殖作用的影响。
二、实验方法
取新生1天的SD大鼠,无菌条件下取脑,分离海马,置于盛有少量高糖DMEM/F12的培养皿中;剥除脑膜及血管组织,将组织尽量剪碎,加细胞培养液5ml,用火焰抛光的Pasteur吸管轻轻吹打制成细胞悬液,400目筛网过滤,胎盼蓝染色计数活细胞的比例,细胞计数后以2×106个细胞/ml的密度接种到25ml的培养瓶。采用基础培养液DMEM/F12(1:1)和B27(2%),并分别加入终浓度分别为10、50、100、200、400μg/ml的马钱素和莫诺苷,将培养板移入37℃、5%CO2、95%空气平衡湿度培养箱中培养,倒置显微镜观察细胞生长状况,微尺测量细胞球直径。
神经干细胞鉴定,取上述细胞球,去除含有生长因子EGF和bFGF的培养液,加含10%FBS的DMEM/F12,种于铺有多聚赖氨酸的24孔培养板中,于16小时时行nestin和doublecortin(DCX)免疫细胞化学染色,细胞几乎均为nestin和doublecortin阳性,说明培养的细胞球是神经干/祖细胞。
三、实验结果
从图1可以看出,用不加生长因子的DMEM/F12培养液培养6天,绝大部分细胞死亡,细胞呈弥散状态。不加生长因子的DMEM/F12培养液中添加马钱素25~200ug/ml,培养6天,神经干细胞球体积增大,为促干细胞存活增殖的有效范围,以50~100ug/ml最佳;莫诺苷25~100ug/ml,神经干细胞球体积增大,为促细胞存活增殖的有效范围,以25~50ug/ml最佳。说明马钱素和莫诺苷可有效促进神经干细胞存活增殖。
实施例2
马钱素和莫诺苷促进神经干细胞分化作用
一、实验目的
观察马钱素和莫诺苷对神经干细胞分化作用的影响
二、实验方法
取第二代神经干细胞球,去除培养瓶内含有生长因子的培养液,细胞球被随机分为2组,①胎牛血清(FBS)对照组:培养液为DMEM/F12+10%FBS;②药物处理组:无FBS培养液DMEM/F12中分别加入终浓度为10、50、100μg/ml的马钱素或莫诺苷,上述两组细胞种于铺有多聚赖氨酸的24孔培养板内,7天后行免疫荧光染色,观察拍照。
三、实验结果
胎牛血清对照组细胞球完全贴壁,单细胞从细胞球周缘迁出,迁出细胞的形态大致可分为两种:①小部分细胞胞体形态接近椭圆形,有2~3个细长的突起;②大部分细胞的胞体较大,形状不规则,突起较多,经免疫细胞化学实验结果分析,分别是神经元、胶质细胞和星形胶质细胞。
无FBS培养液DMEM/F12中分别加入马钱素与莫诺苷的细胞培养板中,10、50μg/ml两组细胞球几乎完全贴壁,分化较好,迁出细胞的细胞的辐射状排列,而是细胞之间互相连接成网状,或几个细胞的突起首尾相连成“串珠状”;100μg/ml组的结果基本相同。结果表明,马钱素与莫诺苷对神经干细胞有良好的促分化作用(图2)。
实施例3
马钱`素与莫诺苷的组合物促进脑损伤后神经干细胞增殖作用
一、实验目的
观察马钱素与莫诺苷组合物对脑卒中大鼠模型神经发生的影响
二、实验方法
SD大鼠,灌胃给予马钱素与莫诺苷组合物(1:1)(大剂量180mg/kg,中剂量60mg/kg,小剂量20mg/kg)7天后用线栓法制作局灶性脑缺血大鼠模型,造模后4~7天内连续腹腔注射给予Brdu(10mg/ml,50mg/kg/次,2次/d)标记内源性增殖的细胞,第8天灌注,固定、取脑,连续冰冻切片,片厚30~40um,行免疫荧光染色。
三、实验结果
正常大鼠海马齿状回(DG)和脑室下层(SVZ)有散在分布的Brdu阳性细胞,阳性细胞胞核着色,多数呈卵圆形;模型组大鼠DG和SVZ的阳性细胞较正常组显著增加;马钱素与莫诺苷组合物大剂量组大鼠的阳性细胞较正常组和模型组增加。说明马钱素与莫诺苷组合物可以促进脑损伤后神经干细胞增殖(图3)。
Claims (5)
1.莫诺苷和马钱素相结合作为仅有的活性成份在制备促进神经干细胞增殖和/或分化的药物中的用途。
2.按照权利要求1的用途,其中所述促进神经干细胞增殖和/或分化是用于治疗神经***变性疾病。
3.按照权利要求2的用途,其中所述疾病为帕金森病、阿尔茨海默病、亨廷顿病、肌萎缩侧索硬化、运动失调病、脊髓源性肌肉萎缩、影响神经***的***性萎缩病、基底节退行性疾病、肌张力障碍或原发性的锥体外系疾病。
4.按照权利要求1的用途,其中所述促进神经干细胞增殖和/或分化是用于治疗中枢神经损伤,所述中枢神经损伤为外伤性、酒精性脑或脊髓损伤。
5.按照权利要求4的用途,其中所述中枢神经损伤为外伤性脑损伤。
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