CN111683656A - 脊髓损伤的预防及治疗用组合物 - Google Patents
脊髓损伤的预防及治疗用组合物 Download PDFInfo
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- CN111683656A CN111683656A CN201980012253.1A CN201980012253A CN111683656A CN 111683656 A CN111683656 A CN 111683656A CN 201980012253 A CN201980012253 A CN 201980012253A CN 111683656 A CN111683656 A CN 111683656A
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Abstract
本发明涉及一种包含(S)‑2‑(((4'‑三氟甲基联苯‑4‑基)甲基)氨基)丙酰胺甲磺酸酯或其药学上可接受的盐作为有效成分的脊髓损伤的预防或治疗用药学组合物等。
Description
技术领域
本发明涉及脊髓损伤的预防及治疗用组合物,具体而言,涉及一种包含(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯的脊髓损伤的预防或治疗用组合物、脊髓损伤的预防或改善用食品组合物,及脊髓损伤的预防或治疗方法等。
背景技术
如果脊髓神经因外伤等而受到损伤,则导致人体功能的麻痹。脊髓神经组织与大脑相比具有单纯的结构,但存在神经再生非常困难的问题。脊髓损伤后出现的病理学现象根据时间大致分为一次性损伤与二次性损伤两个阶段。所谓一次性损伤,是在刚刚损伤后数分钟内出现的现象,伤口部位的细胞坏死(necrosis),在该时期,由于细胞很快被破坏,因而几乎无法通过药物学治疗进行操纵。继一次性损伤之后出现的二次性损伤经数小时至数天内慢慢地进行,并非只有伤口部位的细胞退化,而是在周边的神经细胞和成少突胶质细胞中,根据细胞凋亡(Apoptosis)而慢慢出现细胞死亡。所述细胞死亡以伤口部位为中心持续进行,结果,脊髓内部的损伤部位逐渐扩大。而且,出现作为神经信号移动通路的轴索及帮助轴索功能的髓鞘的退化,结果,形成象孔一样的空闲空间,不能实现进一步的神经信号传递,导致永久性功能消失。
在过去十多年期间,通过对这种脊髓神经外伤后出现的病理作用的原因探查与再生相关研究,进行了旨在抑制或缓解因脊髓损伤导致的永久性功能麻痹的研究。特别是脊髓损伤的初期机制本来就出现地很快,难以利用药物学治疗进行操纵,因而操纵二次机制的药物学战略是治疗剂开发的重要部分。与此相关,迄今尝试了类固醇、抗氧化剂、谷氨酸受体抑制剂、离子通道抑制剂、神经节苷脂(ganglioside)、轴索突起再生抑制剂的抗体、抗炎症剂、神经营养因子等有多样可能性的药物学治疗。其中,现在只有甲泼尼龙作为脊髓损伤后唯一的治疗剂而在使用。但是,众所周知,甲泼尼龙存在治疗效果不明、过量给药导致发生副作用等许多问题,因而迫切需要开发新型治疗剂。
发明内容
技术问题
本发明人为了解决前述问题,经过锐意努力的结果,确认了本发明的(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯化合物表现出恢复因脊髓损伤导致的神经功能下降、缓解疼痛、促进损伤的脊髓组织恢复的效果,从而确认了可以有用地用于脊髓损伤的预防及治疗,从而完成了本发明。
解决问题的方案
本发明的一个目的是提供一种包含以下述化学式1表示的化合物或其药学上可接受的盐作为有效成分的脊髓损伤(spinal cord injury)的预防或治疗用药学组合物。
[化学式1]
本发明的又一目的是提供一种包含所述化合物作为有效成分的脊髓损伤的预防或改善用食品组合物。
本发明的又一目的是提供一种脊髓损伤的预防或治疗方法,包括将所述化合物给药至除人类之外的个体的步骤。
发明效果
确认了本发明的包含化学式1化合物的组合物恢复因脊髓损伤而下降的神经功能,缓解疼痛,促进损伤的脊髓组织的恢复,从而对脊髓损伤的预防、改善及治疗具有优异的效果。
附图说明
图1是显示整体实验期间与药物(KDS2010)给药期间的图。
图2a是向脊髓损伤白鼠和正常白鼠给药KDS2010后确认利用Basso-Beattie-Bresnahan(BBB:巴索-比蒂-布雷纳汉)运动功能评价方式(locomotor rating system)进行行动检查时的神经功能恢复促进效果的图表。
图2b是向脊髓损伤白鼠和正常白鼠给药KDS2010后确认利用动态足底测试(Dynamic plantar test)疼痛反应评价方式来进行疼痛检查时的疼痛反应缓和效果的图表。
图3是向脊髓损伤白鼠和正常白鼠给药KDS2010后,获得组织并通过损伤部位的EC染色来显示出组织的髓鞘化程度的照片,以及在所述照片中测量整个组织的面积、髓鞘化区域的面积、整个组织中的髓鞘化区域的面积%并进行比较的图。
图4a-4d是执行甲苯胺蓝(TB:Toluidine blue)染色及TEM(透射电子显微镜)拍摄而确认髓鞘化轴突的个数、腔洞(cavity)个数及g-比率(g-ratio)值的结果。沙姆(Sham)为未给药脊髓损伤诱导物质的动物模型,V用作KDS的对照组。
图5a-5b为确认免疫荧光染色结果新生成的神经细胞数。
图6通过免疫荧光染色确认的炎症细胞数。
最佳实施方式
对其具体说明如下。另一方面,本发明中公开的各个说明及实施方式也可以应用于各个的其他说明及实施方式。即,本发明公开的多样要素的所有组合属于本发明的范畴。另外,不可以认为本发明的范畴由下述记述的具体叙述所限制。
另外,本技术领域的普通技术人员可以只使用普通实验,认知或确认本发明记载的本发明的特定形态的多个等价物。另外,这些等价物包括于本发明。
本发明的一种方式提供一种包含以下述化学式1表示的化合物或其药学上可接受的盐作为有效成分的脊髓损伤(spinal cord injury)的预防或治疗用药学组合物。
[化学式1]
在本发明中,以所述化学式1表示的化合物是命名为(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯((S)-2-(((4'-trifluoromethyl biphenyl-4-yl)methyl)amino)propanamide methanesulfonate)的化合物。在本发明中,所述化合物可以被命名为KDS2010。
对于所述化合物的具体的药理活性,目前正在研究当中,但尚未明确是否直接具有脊髓损伤的预防及治疗效果。
本发明不特别限定于(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯的获取方法,可以根据本领域公知的方法以化学方式合成,或使用市场销售的物质。
本发明的(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯不仅是以溶剂化的形态,也可以以非-溶剂化的(unsolvated)的形态存在。本发明的(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯可以以晶态或非晶态形态存在,所有这些物理形态均包括于本发明的范围。
本发明的药学组合物不仅是以所述化学式1表示的化合物,也可以包括其药学上可接受的盐。在本发明中,所谓“药学上可接受的盐”是所述化合物与其他物质结合的盐的形态,意味着在药学上能够表现出相似活性的物质。
所述药学上可接受的盐的种类包括诸如盐酸盐、氢溴酸盐、磷酸盐或硫酸盐的无机酸盐和诸如羧酸盐或磺酸盐的有机酸盐,但不限定于此。另外,羧酸盐的种类包括醋酸盐、马来酸盐、富马酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、乳酸盐或苯甲酸盐,但不限定于此。另外,磺酸盐的种类包括甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、甲苯磺酸盐或萘二磺酸盐,但不限定于此。
在本发明中,所谓脊髓损伤(spinal cord injury)为因交通事故或坠落事故等外伤引起脊髓损伤的情形,是指在损伤部位以下因运动神经麻痹而丧失活动能力、失去感觉,且在由自主神经系统调节的膀胱和肠运动调节方面造成异常的疾病。一般而言,脊髓损伤根据损伤程度而分为完全脊髓损伤和不完全脊髓损伤,完全脊髓损伤为脊髓完全横断的状态,是指丧失受损伤的脊髓以下的所有脊髓功能而导致失去运动及感觉能力的损伤。不完全脊髓损伤是指保留了损伤部位以下的一部分感觉或运动功能,因骨骼脱位或软组织、脊髓管内浮肿导致的跌打伤或脊髓部分截断而发生。一般根据损伤部位的位置症状不同,颈椎部位的损伤表现出血压、脉搏、体温、呼吸频率均下降的症状,并出现呼吸困难症状。胸椎和腰椎部位的损伤表现出躯干和四肢的运动、感觉功能丧失及膀胱、大肠及性功能的丧失。
本发明的所述药学组合物可以促进神经功能恢复,或缓解脊髓损伤导致的疼痛,或促进脊髓组织恢复。
在本发明的一个具体实施例中,利用本发明的化学式1的化合物对脊髓损伤动物模型进行处理的结果,与脊髓损伤药物非给药组相比,可以确认神经功能恢复得到促进,疼痛程度得到缓解,脊髓组织的恢复得到促进(图2a、图2b及图3)。
通过所述结果,确认了本发明的包含化学式1的化合物的组合物用作脊髓损伤的预防或治疗用途有优异的效果。
在本发明中,术语“预防”是指通过给药本发明的包含化学式1化合物的组合物来抑制或延迟脊髓损伤发病的所有行为。在本发明中,术语“治疗”是指通过给药本发明的包含化学式1化合物的组合物而使所述疾病的症状好转或有利改善的所有行为。
本发明的脊髓损伤预防或治疗用组合物的药学给药形态,既可以以它们在药学上可接受的盐的形态使用,或者也可以单独或者与其他药学活性化合物结合及以适当的集合来使用。
本发明的脊髓损伤预防或治疗用组合物可以追加包含药学上可接受的载体。
本发明的脊髓损伤预防或治疗用组合物可以使用本领域公知的方法制造成药学剂型,以便给药至哺乳动物后可以提供活性成分的迅速、持续或延迟释放。在剂型的制造方面,优选将活性成分与载体一起混合或稀释,或者封入容器形态的载体内。
因此,本发明的脊髓损伤预防或治疗用组合物根据通常的方法,可以制剂成散剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳剂、糖浆剂、气雾剂等口服剂型、外用剂、栓剂及无菌注射溶液的形态来使用,还可以包括在组合物的制造中通常使用的适合的载体、赋形剂及稀释剂。
例如,本发明的组合物可包含的载体包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石粉、硬脂酸镁及矿物油等,但并不限于此,在进行制剂化的情况下,使用一般使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、界面活性剂等稀释剂或赋形剂来制造。
用于口服给药的固态制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固态制剂在所述化合物中混合至少一种以上的赋形剂,例如淀粉、碳酸钙(calcium carbonate)、蔗糖(sucrose)或乳糖(lactose)、明胶等来制造。另外,除单纯的赋形剂之外,也使用诸如硬脂酸镁、滑石粉的润滑剂。
作为用于口服给药的液态制剂,诸如悬浮剂、内溶液剂、乳剂、糖浆等,除作为常用的单纯稀释剂的水、液体石蜡外,还可以包括多种赋形剂,例如湿润剂、甜味剂、芳香剂、保存剂等。
用于非口服给药的制剂包括灭菌的水溶液、非水性溶剂、悬浮剂、乳剂、冻结干燥制剂、栓剂。作为非水溶性溶剂、悬浮剂,可以使用诸如丙二醇(propylene glycol)、聚乙二醇、橄榄油的植物性油、诸如油酸乙酯的可注射的酯等。作为栓剂的基剂,可以使用witepsol(维特索尔)、聚乙二醇、吐温(tween)61、可可脂、月桂脂、甘油明胶等。
本发明的药学组合物可以作为个别治疗剂给药或与其他治疗剂并用给药,可以与以往的治疗剂依次或同时给药。而且,可以单一或多重给药。重要的是,全部考虑所述要素以不诱发副作用并能够以最小量获得最大效果的量给药,且可以由本领域技术人员容易地决定。
在本发明中使用的术语“给药”是指以某种适当方法向患者导入本发明的药学组合物,本发明组合物的给药途径只要能够到达目标组织,可以通过口服或非口服的多样途径给药。
本发明药学组合物的给药方式不被特别限制,可以遵照相应技术领域通常使用的方式。作为所述给药方式的非限制性示例,可以将组合物以口服给药或非口服给药方式给药。本发明药学组合物可以根据目标给药方式而制作成多样剂型。
本发明组合物的给药频度不特别限定于此,但可以1日1次给药或分割用量数次给药。
本发明的包含化学式1的化合物作为有效成分的组合物的通常1日给药量可以为1至1,000mg/kg,具体而言,可以按11至100mg/kg给药,可以1次或分割为数次给药。
本发明的另一种方式提供一种包含以所述化学式1表示的化合物作为有效成分的脊髓损伤的预防或改善用食品组合物。
本发明的脊髓损伤预防或改善用食品组合物包括丸剂、粉末、颗粒、针剂、片剂、胶囊或液剂等形态,且作为可添加本发明组合物的食品,例如有各种食品类,例如饮料、口香糖、茶、维生素复合剂、保健食品类等。
作为本发明的脊髓损伤预防或改善用食品组合物可包含的必需成分,除所述组合物或其有效成分,或含有其生理学上可接受的盐之外,对其他成分无特别限制,象普通的食品那样,可以含有多种天然药材提取物、食品辅助添加剂或天然碳水化合物等作为追加成分。
正如上述提及的,也可以追加添加食品辅助添加剂,食品辅助添加剂包括本领域通常的食品辅助添加剂,例如香味剂、风味剂、着色剂、填充剂、稳定剂等。
所述天然碳水化合物的示例,为诸如葡萄糖、果糖等单糖、麦芽糖、蔗糖等二糖,以及糊精、环糊精等多糖的通常的糖,以及木糖醇、山梨糖醇、赤藓糖醇等糖醇。除上述内容之外,作为香味剂,可以有利地使用天然香味剂(例如丽鲍迪甙A、甘草甜碱等)及合成香味剂(糖精、阿斯巴甜等)。
除所述内容之外,本发明的脊髓损伤预防或改善用食品组合物可以含有多种营养剂、维生素、矿物质(电解质)、合成风味剂及天然风味剂等风味剂、着色剂及填充剂(奶酪、巧克力等)、果胶酸及其盐、藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、碳酸饮料中使用的碳酸化剂等。此外,可以含有天然果汁及用于生产果汁饮料和蔬菜饮料的果肉。这些成分可以单独使用或组合使用。
在本发明中,所述健康辅助食品包括健康功能食品及健康食品等。
所述所谓健康功能(性)食品(functional food)为与特定保健用食品(food forspecial health use,FoSHU)相同的术语,除供应营养之外,还加工成高效表现生物体调节功能的医学、医疗效果高的食品。其中,所谓“功能(性)”是指针对人体的结构及功能来调节营养素或获得对诸如生理学作用等的保健用途有用的效果。本发明的食品可以根据本领域通常使用的方法制造,在所述制造时,可以添加本领域通常添加的原料及成分而制造。另外,所述食品的剂型,只要是被认定为食品的剂型,则可以无限制地制造。本发明的食品用组合物可以制造成多样形态的剂型,不同于普通药品,以食品为原料,从而具有药品长期服用时没有可能发生的副作用等的优点,便携性卓越,从而本发明的食品可以作为用于增进脊髓损伤预防或改善效果的辅助剂来摄取。
作为本发明的另一种方式,提供一种脊髓损伤的预防或治疗方法,包括将以所述化学式1表示的化合物给药至除人类之外的个体的步骤。
本发明中使用的术语“个体”,可以意味着已发生脊髓损伤或有发生脊髓损伤可能性的包括人类的所有动物。所述动物不仅是人类,还可以是需要治疗与人类类似症状的牛、马、羊、猪、山羊、骆驼、羚羊、狗、猫等哺乳动物,但并不限定于此。
本发明的所述预防及治疗方法具体可以包括:向已发生髓损伤或有发病危险的个体,以药学上有效的量,给药所述组合物的步骤。
具体实施方式
下面通过实施例及实验例,更详细地说明本发明。但是,这些实施例及实验例用于示例性地说明本发明,并非本发明的范围限定于这些实施例及实验例。
实施例1:实验方法
1-1.准备给药物
准备用于确认是否对脊髓损伤具有治疗效果的对象药物。成为给药对象的药物如同韩国授权专利公报第10-1746060号记载所示进行准备。具体而言,根据所述公报记载的合成方法,合成所述公报的实施例9记载的(S)-2-(((4'-三氟甲基联苯-4-基)甲基)氨基)丙酰胺甲磺酸酯(以下称为KDS2010)。
1-2.制作脊髓损伤动物模型
脊髓损伤动物模型使用体重180至200g的成年雄性斯泼累格-多雷大鼠(adultmale Sprague-Dawley rats),且向腹腔注射氯胺酮(ketamine)实施麻醉。针对T9部分执行后屈切除术而使脊髓露出,使用专用钳(self-closed forceps,德国)压迫脊髓10秒钟而使脊髓损伤后,缝合肌肉和皮肤。
1-3.脊髓损伤模型的KDS2010饮水给药及行动、疼痛反应检查
就实验动物管理与研究指南而言,遵照国际实验动物管理评价认证协会(AAALAC)的指南,并在延世大学医学院实验动物部的许可下执行。
整个脊髓损伤动物模型50只中,5只用作药物非给药对照组(Normal),5只用作药物给药对照组(Normal/KDS2010),20只用作脊髓损伤药物非给药组(SCI),20只用作脊髓损伤药物给药组(SCI/KDS2010)。自诱发脊髓损伤的2周后开始将药物与饮用水混合,按10mg/kg用量给药。
就运动功能检查而言,在脊髓损伤后10周期间每周实施一次,共实施10次,使用Basso-Beattie-Bresnahan(BBB:巴索-比蒂-布雷纳汉)检查动物的后腿功能恢复。BBB尺度共分为21分,大致分为3个阶段。在第一恢复阶段,确认关节移动的大小和脚底接触地面与否,在第二恢复阶段,主要观察承载体重的脚步的恢复程度,在最后阶段主要观察步伐的谐调及尾巴的恢复状态。脊髓损伤时伴随的神经性疼痛反应检查利用动态足底触觉计(Dynamic plantar Aesthesiometer),测量了机械性腿回避反应变化,自脚底发生反应的损伤后3周起每周进行。本检查利用直径0.5mm的针,利用0至50g力量,测量后腿的脚底20秒时间。此时,测量了因疼痛而回避脚底时施加的力。
1-4.组织学分析
为了EC染色(Eriochrome(Solochrome)Cyanine staining:依来铬(砂罗铬)氰蓝染色),在脊髓损伤后第10周获得脊髓组织,利用4%多聚甲醛(paraformaldehyde)固定后脱水,实施冻结包埋。EC染色以对照组各5只、脊髓损伤药物非给药组和脊髓损伤药物给药组各10只为对象,在损伤部位(胸椎9号、T9)实施EC染色。
所述EC染色为将髓鞘化的部分染色成蓝色,此外的核、神经、非髓鞘化部位表现为白色,从而可以比较组间组织的面积、髓鞘化部位的染色法。
实施例2:实验结果
2-1.利用Basso-Beattie-Bresnahan(BBB:巴索-比蒂-布雷纳汉)运动功能评价的 神经功能恢复效果确认
如所述实施例1-3所示,对脊髓损伤白鼠和正常白鼠给药KDS2010后,利用Basso- Beattie-Bresnahan(BBB:巴索-比蒂-布雷纳汉)运动功能评价方式(locomotor rating system)进行行动检查。行动检查结果标记为BBB分数。
其结果如图2a所示可知,药物非给药对照组(Normal)、药物给药对照组(Normal/KDS2010)表现出作为正常值的21分,脊髓损伤药物非给药组(SCI)走出了无法承载体重的步伐而表现出10分以下的BBB分数。相反,脊髓损伤药物给药组(SCI/KDS2010),从5周起承载体重,表现出10分以上的分数,最后一周表现出步伐谐调,表明行动功能已恢复。另外,与脊髓损伤药物非给药组相比,确认了BBB分数得到显著恢复。
因此,通过如上所述结果可知,对脊髓损伤模型给药KDS2010药物时,模型动物的神经功能恢复得到促进。
2-2.利用动态足底测试(Dynamic plantar test)疼痛反应评价的疼痛缓解效果
确认
如所述实施例1-3所示,向脊髓损伤白鼠和正常白鼠给药KDS2010后,利用动态足底测试(Dynamic plantar test)疼痛反应评价来评价疼痛缓解程度。
其结果如图2b所示可知,药物非给药对照组(Normal)、药物给药对照组(Normal/KDS2010)对疼痛的阈值(g)高,相反,脊髓损伤药物非给药组(SCI)表现出低阈值。相反,确认了脊髓损伤药物给药组(SCI/KDS2010)相比于脊髓损伤药物非给药组,感觉到疼痛的阈值显著增加。
因此,通过如上所述结果可知,向脊髓损伤模型给药KDS2010药物时,模型动物的疼痛程度得到缓解。
2-3.脊髓组织的恢复促进效果的确认
如所述实施例1-4所示,以药物非给药对照组、药物给药对照组、脊髓损伤药物非给药组、脊髓损伤药物给药组为对象,对损伤部位(胸椎9号、T9)进行EC染色,对髓鞘化部位的结果进行了定量化。
其结果如图3可知,药物非给药对照组(Control)、药物给药对照组(Control/KDS2010)确认了整个脊髓组织的面积、髓鞘化区域面积、整个组织中髓鞘化区域面积大,而脊髓损伤药物非给药组(SCI)分别均表现出较低数值。这种结果表明由于脊髓损伤,脊髓组织的面积、髓鞘化区域的面积均减小。
相反,脊髓损伤药物给药组(SCI/KDS2010)相比于脊髓损伤药物非给药组,确认了脊髓组织面积、髓鞘化区域面积增加。
因此,通过如上所述结果可知,对脊髓损伤模型给药KDS2010药物时,模型动物的脊髓组织恢复效果得到促进。
2-4.脊髓损伤区域的再髓鞘化效果的确认
为了更详细地确认实施例2-3中确认的结果而执行了追加分析。
具体而言,执行Toluidine blue(TB:甲苯胺蓝)染色及TEM拍摄,确认髓鞘化轴突(axon)的个数、腔洞(cavity)个数及g-ratio值。
结果如图4所示可以确认,因脊髓损伤而减少的髓鞘化轴突,由于KDS2010而恢复为接近正常(图4a),相反,因脊髓损伤而大大增加的腔洞数,KDS2010处理时可以急剧减少(图4b)。另外,g-ratio是作为确认所恢复的髓鞘化轴突的正常传导性(conductivity)与传递速度(velocity)的尺度。测量g-ratio的结果,确认了脊髓损伤模型大大超出作为正常范围的0.79±0.005,但KDS2010具有正常范围的g-ratio值。
因此,通过如上所述结果可知,对脊髓损伤模型给药KDS2010药物时,促进了再髓鞘化现象而表现出脊髓组织恢复效果。
2-5.脊髓神经再生效果的确认
为了确认脊髓神经再生效果,执行了旨在确认进行KDS2010处理时是否具有分化新神经细胞的效果的实验。
具体而言,将BrdU以50mg/kg/day用量,通过腹腔注射(i.p injection),在处死1周期间前注入至实验动物后,对脊髓神经执行免疫荧光染色并进行观察。
结果如图5所示,确认了脊髓损伤模型的新细胞生成被抑制,出现神经细胞损失,相反,在进行KDS2010处理的动物模型中,以新的方式形成神经细胞。
因此,通过如上所述结果可知,KDS2010药物促进脊髓的神经细胞生成,在脊髓损伤时,对神经再生作出贡献。
2-6.脊髓损伤组织中的炎症反应抑制效果的确认
脊髓出现损伤时,以损伤部位为中心向内侧观察到细胞破坏物和细胞集团,这些细胞诱发炎症反应,会妨碍脊髓损伤后的再生。执行了用于确认KDS2010药物对这种炎症反应的效果的实验。
具体而言,在脊髓损伤模型及KDS2010给药组中,通过荧光染色,确认作为巨噬细胞标记物的CD68和作为小胶质细胞标记物的Iba1是否为阳性。
结果如图6所示,确认了在脊髓损伤模型中,在KDS2010给药组中,CD68和Iba1的阳性细胞显著减少。
因此,通过如上所述结果可知,通过给药KDS2010,可以抑制成为脊髓再生的抑制原因的炎症细胞数。
从以上说明可以理解,本发明所属技术领域的技术人员可以在不变更本发明的技术思想或必需特征的情况下以其他具体形态实施。与此相关,以上记述的实施例在所有方面应理解为只是示例性的而非限定性的。应解释为,本发明的范围,相比于所述详细说明,从后述权利要求书的意义及范围以及其等价概念导出的所有变更或变形的形态均包含于本发明的范围。
Claims (7)
2.根据权利要求1所述的组合物,其中,
所述脊髓损伤为外伤性脊髓损伤或非外伤性脊髓损伤。
3.根据权利要求1所述的组合物,其特征在于,
所述组合物促进因脊髓损伤而减少的神经功能的恢复。
4.根据权利要求1所述的组合物,其特征在于,
所述组合物缓解由脊髓损伤引起的疼痛。
5.根据权利要求1所述的组合物,其中,
所述组合物促进脊髓组织恢复。
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