CN109966278A - 草酰苹果酸在制备治疗神经细胞损伤的药物中的应用 - Google Patents
草酰苹果酸在制备治疗神经细胞损伤的药物中的应用 Download PDFInfo
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Abstract
本发明涉及草酰苹果酸在制备治疗神经细胞损伤的药物中的应用。将草酰苹果酸用于治疗缺血再灌注损伤，尤其是治疗脑组织神经病，更尤其是对缺血性脑卒中的保护作用，能显著减轻脑缺血/再灌注损伤，减少脑神经细胞损伤和提高神经细胞功能。
Description
技术领域
本发明涉及草酰苹果酸在制备治疗神经细胞损伤的药物中的应用，属于生物医药领域。
背景技术
缺血脑卒中是严重危害人类健康的常见和多发病，在全球已成为第一致残和第三致死的原因，缺血性脑卒中的发病率约占脑血管病的70-80％。
脑缺血损伤与自由基过度形成、兴奋性氨基酸毒性作用、细胞内钙超载、炎性反应等多种机制有关，无论何种机制，最终的结局都会导致神经细胞死亡、功能破坏、脑梗死灶形成。细胞死亡的方式主要有坏死和凋亡两条途径。传统观点认为，坏死是一种随机的、意外的和不受调控的被动死亡方式，而凋亡则是一种受到严密调控的主动死亡方式。最近的研究表明，坏死也受到各种信号通路严密调控，称为调节性坏死，包括坏死性凋亡(necroptosis)，CypD依赖的坏死等。其中，RIPK1/RIPK3/MLKL 依赖的坏死性凋亡最受关注。研究表明，RIPK1/RIPK3/MLKL依赖的坏死性凋亡存在于多种损伤相关性疾病中，包括心肌梗死和缺血性脑卒中。因此，抑制RIPK1/RIPK3依赖的坏死性凋亡已成为目前减轻缺血性脑卒中神经细胞死亡的有效途径。文献报道，RIPK1抑制剂necrostatin-1(Nec-1)能减少小鼠脑缺血损伤，改善神经功能，该作用与抑制神经细胞的坏死性凋亡密切相关。然而，Nec-1仅作为工具药用于动物实验，目前临床上尚无针对RIPK1/RIPK3/MLKL药物用于治疗缺血性脑卒中，也未见草酰苹果酸治疗缺血性脑卒或神经细胞损伤中的报道。
发明内容
针对现有技术的不足，本发明提供草酰苹果酸在制备治疗神经细胞损伤的药物中的应用。
本发明所述草酰苹果酸的结构式如下式所示：
分子式为：C6H3O8；分子量为：272.05。
进一步地，所述神经细胞包括中枢神经系统疾病相关神经细胞。
进一步地，所述中枢神经系统疾病包括外伤性中枢神经系统损伤、脑损伤、脊髓损伤、脑卒中、神经退行性疾病、阿尔茨海默病、亨廷顿病、痴呆、肌萎缩侧索硬化、帕金森病、多发性硬化症、糖尿病性神经病、脊髓小脑共济失调、fahr病、menke病、威尔逊病、脑缺血、朊病毒病、额颞叶痴呆、路易体痴呆、皮质基底部退化、进行性核上性麻痹、多系统萎缩和遗传性痉挛性截瘫。
进一步地，所述脑卒中包括缺血性脑卒中和/或出血性脑卒中。
进一步地，所述缺血性脑卒中包括脑缺血/再灌注损伤。
进一步地，所述缺血/再灌注损伤还包括心肌缺血/再灌注损伤、肝缺血/再灌注损伤、肾缺血/再灌注损伤、肺缺血/再灌注损伤中的一种或几种。
进一步地，所述药物可以按照已知技术制备成任意一种药剂学上可以接受的剂型，如口服剂、注射剂、片剂、胶囊剂、颗粒剂、散剂、口服液或滴丸,优选为口服剂。
进一步地，所述药物的剂型为口服剂。
可选地，所述应用中的给药方式为皮下注射、静脉注射、肌肉注射、口服给药或黏膜给药。
可选地，所述应用中的给药方式为口服给药。
本发明通过实验表明，草酰苹果酸能特异性下调磷酸化MLKL水平，抑制神经细胞坏死样凋亡，显著降低脑缺血梗死体积和神经生物学评分，减少脑神经细胞死亡和提高神经细胞功能。因此，草酰苹果酸可应用于制备治疗缺血/再灌注损伤的药物。
本发明通过实验表明，草酰苹果酸显著降低脑缺血梗死体积和神经生物学评分，减少脑神经细胞死亡和提高神经细胞功能，可应用于制备中枢神经系统疾病所致脑神经细胞受损和神经功能失调，所述中枢神经系统疾病包括外伤性中枢神经系统损伤、脑损伤、脊髓损伤、神经退行性疾病、阿尔茨海默病、亨廷顿病疾病、痴呆、肌萎缩侧索硬化、帕金森病、多发性硬化症、糖尿病性神经病、不同类型脊髓小脑共济失调、fahr病、menke病、威尔逊病、脑缺血、朊病毒紊乱、额颞叶痴呆、路易体痴呆、皮质基底部退化、进行性核上性麻痹、多系统萎缩和遗传性痉挛性截瘫。
本发明扩大了草酰苹果酸的适应症，可适用于缺血/再灌注损伤；与注射给药方式相比，本发明可采用口服给药，操作简单，刺激性小，增强病人的依从性。
草酰苹果酸用于治疗脑卒中尚未见报道。本发明首次将草酰苹果酸用于治疗大鼠缺血性脑卒中模型，发现草酰苹果酸能下调大鼠脑组织中磷酸化MLKL水平，降低大鼠脑梗死体积，减少神经细胞损伤和改善神经学功能。本发明首次证明草酰苹果酸可以用于治疗缺血性脑卒中，其机制通过下调 MLKL磷酸化水平，抑制神经细胞坏死性凋亡而发挥作用。本发明扩大草酰苹果酸适应症范围，发现了其新的药物作用机制。缺血性脑卒中为临床常见病，草酰苹果酸具有广阔的应用前景。
本发明人的研究发现草酰苹果酸具有新的功能，能特异性下调磷酸化MLKL水平,抑制细胞坏死性凋亡。
总之，本发明将草酰苹果酸用于治疗脑组织神经病，尤其是对缺血性脑卒中的保护作用，能显著减轻脑缺血/再灌注损伤。
附图说明
图1：手术前15分钟给药，A-大鼠脑组织TTC染色及梗死体积测定，B-大鼠神经学功能评分。
具体实施方式
动物实验：草酰苹果酸对缺血性脑卒中的保护作用
实施药品：草酰苹果酸购于试剂公司。
将草酰苹果酸用生理盐水溶解。
实验动物：体重250～300g的健康雄性SD大鼠。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验要求，给药组口服给药。
建模方法：用脑中动脉阻塞(MCAO)法制备大鼠脑缺血/再灌注损伤模型。步骤如下：(1)分离颈外动脉(CCA)，向上分离左颈外动脉(ECA)与颈内动脉(ICA)；(2)用眼科镊暂时夹闭ECA和ICA，并结扎CCA近心端；(3)于CCA远心端放置一打好结的备用丝线，在此线下端剪一小口，将栓线插入至颈内动脉，收紧丝线，放开ECA和ICA上的动脉夹，顺ICA将栓线送至颅内；(4)遇阻力而止, 从CCA分叉处算起，插入深度约为18～20mm；(5)缺血120min后，将栓线拔出，缝好皮肤，再灌注24h后处理动物。
模型成功评判标准采用Longa“5分法”对大鼠脑缺血损伤的神经功能缺损进行评分。0分：无神经缺损症状；1分：右前肢不能完全伸直；2分：向右旋转；3分：行走向右侧倾倒；4分：不能自发行走，意识丧失。1～4分为有效模型。
大鼠脑TTC染色和梗死体积测定。大鼠麻醉后，迅速将脑取出，去掉嗅球及后脑，从额极开始切取4张冠状脑片，厚约2.0mm，立刻置于1％TTC溶液中，37℃避光孵育30min。然后用10％多聚甲醛溶液浸泡固定。梗死区呈现白色，非梗死区呈现红色。将每组脑片排列整齐后进行扫描。再应用ImageJ测出各脑片的梗塞面积，根据公式：梗死体积＝[(各片正面梗死面积之和+各片反面梗死面积之和)/2]×每片厚度,同样方法计算出全脑体积。
实验分组：将实验动物随机分为4组，即：
对照组(control组)：不做任何处理。
假手术组(sham组)：分离血管后不插入栓线。
缺血/再灌注组(I/R)：脑缺血2h，再灌注24h。
草酰苹果酸+脑缺血/再灌注组(OMA+I/R)：手术前15分钟灌胃草酰苹果酸(用量：10mg/kg),然后脑缺血2h，再灌注24h。
检测指标：大鼠神经功能评分和梗死体积测定。
实验结果
草酰苹果酸对大鼠脑梗死体积及神经功能的影响
图1中的A所示，I/R组有明显的白色梗死灶，而手术前给予草酰苹果酸组大鼠脑梗死灶显著缩小，明显缓解脑缺血损伤(p<0.01)。图B，脑缺血组(I/R)大鼠出现明显的神经运动功能障碍，而草酰苹果酸可明显改善神经功能缺损症状(p<0.01)。
但本专利不局限于脑缺血/再灌注损伤，因心、肝和肾缺血/再灌注损伤同样存在坏死样凋亡，故该药同样适用于治疗心、肝、肾和肺缺血/再灌注损伤。另外，中枢神经系统疾病中坏死样凋亡上调导致脑神经细胞受损和神经功能失调，因此草酰苹果酸也适用于治疗这些中枢系统疾病。
Claims (8)
1.草酰苹果酸在制备治疗神经细胞损伤的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述神经细胞包括中枢神经系统疾病相关神经细胞。
3.根据权利要求2所述的应用，其特征在于，所述中枢神经系统疾病包括外伤性中枢神经系统损伤、脑损伤、脊髓损伤、脑卒中、神经退行性疾病、阿尔茨海默病、亨廷顿病、痴呆、肌萎缩侧索硬化、帕金森病、多发性硬化症、糖尿病性神经病、脊髓小脑共济失调、fahr病、menke病、威尔逊病、脑缺血、朊病毒病、额颞叶痴呆、路易体痴呆、皮质基底部退化、进行性核上性麻痹、多系统萎缩和遗传性痉挛性截瘫。
4.根据权利要求3所述的应用，其特征在于，所述脑卒中包括缺血性脑卒中和/或出血性脑卒中。
5.根据权利要求4所述的应用，其特征在于，所述缺血性脑卒中包括脑缺血/再灌注损伤。
6.根据权利要求5所述的应用，其特征在于，所述缺血/再灌注损伤还包括心肌缺血/再灌注损伤、肝缺血/再灌注损伤、肾缺血/再灌注损伤、肺缺血/再灌注损伤中的一种或几种。
7.根据权利要求1-6任一项所述的应用，其特征在于，所述药物可以制备成药剂学上可以接受的任意一种剂型，进一步地，所述剂型包括口服剂、注射剂、片剂、胶囊剂、颗粒剂、散剂、口服液、滴丸，优选为口服剂或注射剂。
8.根据权利要求7所述的应用，其特征在于，所述药物的剂型为口服剂。
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