CN112807321A - 治疗脑缺血再灌注损伤的组合物及其应用 - Google Patents
治疗脑缺血再灌注损伤的组合物及其应用 Download PDFInfo
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- CN112807321A CN112807321A CN202110052551.2A CN202110052551A CN112807321A CN 112807321 A CN112807321 A CN 112807321A CN 202110052551 A CN202110052551 A CN 202110052551A CN 112807321 A CN112807321 A CN 112807321A
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Abstract
本发明提供治疗脑缺血再灌注损伤的组合物，其包含β‑烟酰胺单核苷酸(NMN)和L‑α‑甘油磷酸胆碱(α‑GPC)，其中，按照L‑α‑甘油磷酸胆碱的使用剂量为15～25mg/kg/d、β‑烟酰胺单核苷酸的使用剂量为10～30mg/kg/d给药。在经典的MCAO模型中，本发明组合物对人工造模后MCAO大鼠的神经行为学有着改善作用。
Description
技术领域
本发明涉及一种治疗脑缺血再灌注损伤的组合物及其应用。
背景技术
脑中风是一组以脑部缺血及出血性损伤症状为主要临床表现的疾病，又称脑卒中或脑血管意外，具有极高的病死率和致残率，主要分为出血性脑中风(脑出血或蛛网膜下腔出血)和缺血性脑中风(脑梗塞、脑血栓形成)两大类，其中，以脑梗塞最为常见。脑中风发病急，病死率高，是世界上最重要的致死性疾病之一。脑是人类的重要器官之一，其重量仅为体重的2％，但其耗氧量则占全身耗氧量的20％，其所需血供占心输出量的15％，因此对氧和血的要求特别高，极易受到缺血性损害，其中由大脑中动脉梗塞造成的脑缺血尤为常见。中华人民共和国卫生部官方网站提供的统计数据显示，2003年脑血管疾病在城市和农村疾病死亡原因中均排名第二位，仅次于恶性肿瘤。脑血管病包括缺血性和出血性脑血管病，其中缺血性脑血管病占80～85％。
中风的死亡率也有随年龄增长而上升的趋势，由于一直缺乏有效的治疗措施，目前认为预防是最好的措施，因此，加强对全民普及脑中风的危险因素及先兆症状的教育，才会真正获得有效的防治效果。然而天有不测风云，罹患中风的病患如何更好的康复一直备受关注，脑中风，特别是缺血性脑中风之后的神经保护、神经修复类医药也是医药界重要的研究课题。目前神经保护剂分为以下几类：(1)离子通道调节剂：如钙离子通道拮抗剂尼莫地平、桂派齐特、法舒地尔；钠离子通道拮抗剂长春西汀；钾离子通道激活剂吡那地尔、尼可地尔、色满卡林。(2)作用于细胞水平的脑保护剂(稳定细胞膜和提供能量)：如胞磷胆碱、三磷酸胞苷、小牛血清提取物、己酮可可碱。(3)兴奋性氨基酸受体拮抗剂：如神经节苷脂、醋谷胺(乙酰谷酰胺)。(4)γ-氨基丁酸(GABA)受体激动剂：如氯美噻唑。(5)自由基清除剂与抗氧化剂：如依达拉奉。(6)其他神经保护剂：如中药制剂丹参、刺五加等，以及一氧化氮合酶抑制剂、神经营养因子、腺转运抑制剂等。然而，仍需要开发更多的安全有效的治疗脑缺血再灌注损伤的药物。
发明内容
本发明的目的是开发一款可以适合长期服用并能够预防或改善脑缺血再灌注损伤组合物。本发明的发明人经过深入研究，意外地发现将NMN和α-GPC组合使用，显示了脑缺血再灌注损伤的改善作用，从而完成了本发明。本发明的组合物，可以应用于制备用于治疗脑缺血再灌注损伤的药物，或者以预防和治疗为目的功能性食品。
具体而言，本发明提供一种具有神经保护作用的组合物，其特征在于，其包含L-α-甘油磷酸胆碱(α-GPC)和β-烟酰胺单核苷酸(NMN)，其中，β-烟酰胺单核苷酸的使用剂量为10～30mg/kg/d，L-α-甘油磷酸胆碱的使用剂量为15～25mg/kg/d。
作为本发明优选实施方式的药物制剂，可以为片剂、胶囊剂。
本发明还提供一种功能性食品，包含上述的具有神经保护作用的组合物以及可食用的辅料。
本发明的组合物，可以应用于制备用于治疗脑缺血再灌注损伤的药物。
本发明中的α-GPC是L-α-甘油磷酸胆碱的简称，其是具有由构成细胞膜的主要磷脂PC(磷脂酰胆碱)脱去2个脂肪酸后的水溶性物质，原本在生物体内广泛存在，是存在于人的母乳及体液肿的身体成分之一，2009年的食品药品分类修订中，将L-α-甘油磷酸胆碱(有时也可以称为sn-甘油-3-磷酸胆碱)定义为食品。α-GPC为可以通过血脑屏障少数几种营养素之一，因此可以迅速的从胆碱转换为乙酰胆碱，被认为是防止胆碱缺乏、增加神经递质、促进促生长激素的分泌等的营养素。然而，可能是由于单纯的摄入α-GPC营养品由于机体的调控作用，目前为止尚没有α-GPC的摄入能够治疗或者改善脑缺血导致的神经损伤的症状的报道。
NMN(Nicotinamide mononucleotide)是β-烟酰胺单核苷酸的简称，人体细胞中天然存在，为辅酶1NAD+的前体。可适当延长寿命。真正发挥抗衰老作用的是一种称为烟酰胺腺嘌呤二核苷酸(NAD+)的重要能量代谢物。NMN是一种营养物质，市场上可以获得商品。NMN会在细胞中转化为NAD+，它归类为一种全新的维生素B3，且超越了普通维生素的功效，被认为是预防衰老和恢复年轻的补充剂。NMN本身是人体内含有的物质，存在于母乳及食物中，例如毛豆、西兰花、黄瓜、圆白菜、鳄梨、番茄等，但含量非常少(每100克中含有0.25-1.88毫克)。生牛肉和虾等也含有非常少量的(每100克中含有0.06-0.42毫克)NMN成分。所以想要提高NMN，还要从外界直接补充。NMN一般认为主要通过:增加高密度脂蛋白、减少低密度脂蛋白、被氧化、减轻巨噬细胞的炎症反应、减少粥样硬化斑块的形成、增加粥样硬化斑块的稳定性、减少斑块破裂,改善血流等上述方式来防治心血管疾病。但是迄今为止，尚无直接证据证实NMN的摄入能够治疗或者改善脑缺血导致的神经损伤的症状。
然而本发明的发明人意外地发现，将NMN和α-GPC这两种内源性的营养成分组合使用，在动物模型上显示了一定程度改善脑缺血导致的神经损伤的症状的作用，提示了NMN和α-GPC合用作为预防或具有神经保护作用的前景，具体可以参见实施例中的具体实施例。
作为本发明的优选的实施方式，本发明还提供一种具有神经保护作用的药物制剂，其包含上述组合物，还包含药学上可用接受的辅料。
本发明的组合物在使用时，优选制成口服给药的固体剂型来给药。作为用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，将组合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，组合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了本发明组合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了本发明组合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
从服用方便角度考虑，本发明的组合物优选制成片剂或者胶囊剂。为制备本发明组合物的粉剂的片剂或胶囊，可将本发明组合物的粉剂与制剂载体混合，该载体为常用的制片剂组分，如玉米淀粉、蔗糖、山梨醇、脂肪酸、硬脂酸镁和其它药用稀释剂。
本发明的具有神经保护作用的组合物，可以与其他类的具有神经保护作用的药物合用。作为其他的神经保护的药物，可举出尼莫地平、桂派齐特、法舒地尔；钠离子通道拮抗剂长春西汀、吡那地尔、尼可地尔、色满卡林、胞磷胆碱、三磷酸胞苷、小牛血清提取物、己酮可可碱、神经节苷脂、醋谷胺(乙酰谷酰胺)、如氯美噻唑、依达拉奉等临床常见的药物。
本发明还提供一种功能性食品，包含上述的具有神经保护作用的组合物以及可食用的辅料。
由于本发明的组合物由于原料完全可食用，非常适合开发成功能食品，例如可制备成口含片、糖果、固体饮料、液体饮料形式的功能性食品。本发明的功能性食品，包含本发明的上述组合物和可食用的辅料，作为可以使用的符合相关标准的食品添加剂，例如符合中华人民共和国GB2760-2014标准的食品添加剂
作为本发明的功能性食品的优选形式，可以举出口含片。将本发明的组合物制成口含片的方式没有特殊限制，可以使用公知的方法，例如，将本发明的组合物的造粒，添加可食用的辅料等混合，进行压片的过程。作为可食用的辅料，可以举出淀粉、蔗糖、甲基纤维素低聚果糖、茶粉、食盐、甜菊糖苷、山梨糖醇、维生素C等，但不限于这些，只要是符合GB2760-2014或其他国家的相关食品标准的辅料均可以适当添加。
本发明的组合物为了利于食用、利于防止吸潮等目的，也可以包衣。从食品角度出发，优选使用海藻酸钠、黄原胶、阿拉伯胶等完全符合食品标准的辅料进行包衣。
作为本发明的功能性食品的优选形式，从食品化观感强，接受度高的角度考虑，本发明的组合物，还可以制成食品口服液的形式。作为食品口服的液体制剂的剂型有溶液、糖浆或混悬液。这些液体制剂的制备方法中，分散媒一般为水，非水溶性的赋形剂如杏仁油、油脂；作为药剂学上允许使用的填加剂包括如山梨醇、氢化食用油、甲基纤维素；还包括防腐剂如甲基或丙基P-酚；乳化剂如卵磷脂、阿拉伯橡胶：人工色素或甜味剂。
作为给药的剂量，应根据对象的年龄、体重、健康状况及剂型的不同而定。推荐的使用剂量为β-烟酰胺单核苷酸的使用剂量为10～30mg/kg/d，L-α-甘油磷酸胆碱的使用剂量为15～25mg/kg/d。但是由于本发明的原料成分均有着很强的安全性，本领域的技术人员可以根据个体需要，适当增加各组分有效用量。优选的使用量为β-烟酰胺单核苷酸的使用剂量为20mg/kg/d，L-α-甘油磷酸胆碱20mg/kg/d。
本发明的发明人通过实验动物模型，验证了本发明的组合物的具有治疗脑缺血再灌注损伤的药效。具体而言，本研究中采用利用经典的大鼠MCAO模型验证本发明组合物的活性效果。所谓的MCAO(middle cerebral artery occlusion)模型是人工方法将大鼠或小鼠等试验的脑动脉栓塞，结合神经行为学评价，从而评价给药成分的效果的模型。单独利用NMN灌胃大鼠没有表现出行为学上的症状改善，同样地，单独利用α-GPC灌胃大鼠也未表现行为学上的症状改善。然而，当组合使用NMN和α-GPC进行灌胃时，意外地发现对于MCAO模型大鼠表现出了行为学上的症状改善，提示了组合使用NMN和α-GPC具有预防或具有神经保护作用的应用前景。
本发明的组合物与现有技术相比，存在以下明显的优势：本发明所开发的组合物的原料均为食品，是效果明确、安全性令人信服的具有神经保护作用的组合物，本发明的组合物并采用科学的动物表型验证了确切的效果，考虑到其特别适合以满足可以适合长期服用，因此虽然其效果不强，用于预防神经保护症状仍然有着广阔的市场前景。
具体实施方式
以下结合具体的实施例对本发明进行进一步详细的描述，实施例仅仅是为了说明本发明技术方案的实例，并非为了对本发明的保护范围进行任何限定。
实施例1大鼠MCAO模型的建立
本发明中利用经典的大鼠MCAO模型验证本发明组合物的活性效果。所谓的MCAO(middle cerebral artery occlusion)模型是人工方法将大鼠或小鼠等试验的脑动脉栓塞。具体的建模方法参照如下所示。
造模流程：作为受试动物，使用SD大鼠，8周龄(250g-350g体重)雄性，购自北京维通利华实验动物公司。SD大鼠40只，适应性喂养1周后，每组8只，随机分为5组：sham组(假手术组，仅切开表皮不进行血管结扎)、模型组、NMN组(给药NMN 20mg/kg/d)、α-GPC组(给药α-GPC 20mg/kg/d)、组合物(NMN20mg/kg/d和α-GPC 20mg/kg/d)组。除了sham组，其余各组均进行下述的手术建模
造模过程为，准备眼科剪、弯镊1对、(动脉夹2)、止血钳2-3、缝合线、缝合针、棉球、75％酒精、生理盐水、注射器(1ml)、大鼠板，麻醉剂采用7％水合氯醛。将大鼠称重，0.5ml/100g麻醉剂进行麻醉。将大鼠用医用胶带固定于操作台上，颈部剃毛。MCAO栓线采用2434型号尼龙栓线(购自于北京西浓)。颈部酒精棉球消毒，眼科剪沿锁骨正中做竖向切口。分离皮下肌肉组织，找到肌肉下方有轻微搏动血管即为颈总动脉，钝性分离覆盖于颈总动脉上方的肌肉，分离出颈总动脉后，眼科镊小心分离伴行于颈总动脉的迷走神经，还需要分离干净动脉周围粘膜组织，分离出右侧颈总动脉(CCA)、颈内动脉(ICA)及颈外动脉(ECA)，靠尾部结扎颈总动脉(CCA)。再结扎颈外动脉(ECA)，两个结扎之间备线，打松结。在ECA剪开切口，插入尼龙线，致使大脑中动脉阻塞缺血。1.5小时后，用眼科镊夹住栓线固定处将栓线拔出至其头端，放开CCA丝线，剪去多余栓线，逐层缝合，消毒；假手术组仅剥离颈总动脉后立即缝合创口。
实施例2利用大鼠MCAO模型进行的神经行为学评价
上述手术后放回笼子，各组大鼠灌胃给与相应的受试药物，并给予充足饲料和水。手术24小时后，通过目视观察各组大鼠的神经行为学状况，依据longa 5分制量表统计各组大鼠神经行为学评分，各组大鼠脑神经行为学评分(平均值±标准差)汇总在表1中。
评分标准如下：
0分：活动基本正常，无明显神经病学症状；
1分：左侧前爪无法完全伸展；
2分：爬行时向左侧转圈；
3分：行走时向偏瘫侧倾倒；
4分：不能自动行走，有意识障碍
5分：死亡
表1各组大鼠脑神经行为学评分(平均值±标准差)
模型组、NMN组与α-GPC组，与假手术组比较，P<0.01；组合物组与模型组比较，P<0.05。组合物组显示了对于脑缺血再灌注模型大鼠，在神经行为学上的改善作用。提示其可能存在相应的神经保护效果，能够用于治疗脑缺血再灌注损伤。
实施例3TTC染色
取各组大鼠利用10％水合氯醛腹腔注射麻醉，迅速断头取脑。取缺血再灌注侧大脑半球中部，同位置切出6片2mm的切片，在暗室中，用2％氯化三苯基四氮唑(TTC)染色15分钟，用10％福尔马林固定一夜，非缺血区呈玫瑰红色，拍摄照片，使用Image-Pro Plus计算机软件进行图像处理，计算脑相对缺血面积，汇总在表2中。
表2各组大鼠脑相对缺血面积(平均值±标准差)
组合物组显示了较少的缺血区域，与其他组存在显著性差异。
本说明书中引用的所有出版物和专利文献引入本文作为参考，如同每个出版物或专利被分别明确指明引入本文作为参考。在不偏离本申请公开的实质和范围的情况下，可对本申请公开的各实施方案进行多种改变和用等同物替换。除非上下文中另有说明，否则本公开的实施方案的任何特征、步骤或实施方案都可以与任何其他特征、步骤或实施方案组合使用。最后应说明的是：以上所述的各实施例仅用于说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分或全部技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (7)
1.由β-烟酰胺单核苷酸NMN和L-α-甘油磷酸胆碱α-GPC构成的组合物，在制备用于治疗脑缺血再灌注损伤的药物中的应用。
2.根据权利要求1所述的应用，所述治疗脑缺血再灌注损伤的药物为治疗中风后遗症的药物。
3.一种治疗脑缺血再灌注损伤的组合物，其特征在于，其包含L-α-甘油磷酸胆碱α-GPC和β-烟酰胺单核苷酸NMN，其中，β-烟酰胺单核苷酸的使用剂量为10～30mg/kg/d，L-α-甘油磷酸胆碱的使用剂量为15～25mg/kg/d。
4.一种治疗脑缺血再灌注损伤的药物制剂，其特征在于，其包含权利要求1中所述的具有神经保护作用的组合物，以及药学上可用接受的辅料。
5.根据权利要求4所述的药物制剂，其为片剂、胶囊剂。
6.一种功能性食品，包含权利要求3所述的治疗脑缺血再灌注损伤的组合物以及可食用的辅料。
7.权利要求3所述的组合物，在改善脑缺血再灌注MCAO模型大鼠的神经行为学表现中的应用。
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Citations (4)
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|---|---|---|---|---|
| US20120184607A1 (en) * | 2009-09-24 | 2012-07-19 | Huayin Wan | Use of piperphentonamine or salts thereof in manufacture of madicaments for prevention/treating brain diseases |
| US20140343865A1 (en) * | 2011-12-09 | 2014-11-20 | Meredith V. Brown | Biomarkers for Kidney Cancer and Methods Using the Same |
| AU2016200507A1 (en) * | 2009-09-15 | 2016-02-18 | Cerulean Pharma Inc. | Treatment of cancer |
| WO2017015660A1 (en) * | 2015-07-23 | 2017-01-26 | Salk Institute For Biological Studies | Prevention and treatment of aging and neurodegenerative diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2016200507A1 (en) * | 2009-09-15 | 2016-02-18 | Cerulean Pharma Inc. | Treatment of cancer |
| US20120184607A1 (en) * | 2009-09-24 | 2012-07-19 | Huayin Wan | Use of piperphentonamine or salts thereof in manufacture of madicaments for prevention/treating brain diseases |
| US20140343865A1 (en) * | 2011-12-09 | 2014-11-20 | Meredith V. Brown | Biomarkers for Kidney Cancer and Methods Using the Same |
| WO2017015660A1 (en) * | 2015-07-23 | 2017-01-26 | Salk Institute For Biological Studies | Prevention and treatment of aging and neurodegenerative diseases |
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