CN109966278A - Application of oxalylmalic acid in the preparation of drugs for the treatment of nerve cell injury - Google Patents
Application of oxalylmalic acid in the preparation of drugs for the treatment of nerve cell injury 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。
The present invention relates to the application of oxalylmalic acid in preparing medicine for treating nerve cell damage. The use of oxalylmalic acid for the treatment of ischemia-reperfusion injury, especially the treatment of cerebral neuropathy, especially the protection of ischemic stroke, can significantly reduce cerebral ischemia/reperfusion injury and reduce brain nerve cell damage and improve nerve cell function.
Description
技术领域technical field
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。The invention relates to the application of oxalylmalic acid in the preparation of a medicine for treating nerve cell damage, and belongs to the field of biomedicine.
背景技术Background technique
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％。Ischemic stroke is a common and frequently-occurring disease that seriously endangers human health. It has become the first cause of disability and the third cause of death in the world. The incidence of ischemic stroke accounts for about 70-80% of cerebrovascular diseases.
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。Cerebral ischemic injury is related to various mechanisms, such as excessive formation of free radicals, the toxicity of excitatory amino acids, intracellular calcium overload, and inflammatory reactions. Regardless of the mechanism, the final outcome will lead to nerve cell death, functional destruction, and cerebral infarction. form. There are two main ways of cell death: necrosis and apoptosis. The conventional view is that necrosis is a random, accidental and unregulated passive mode of death, whereas apoptosis is a tightly regulated active death mode. Recent studies have shown that necrosis is also tightly regulated by various signaling pathways, called regulated necrosis, including necroptosis and CypD-dependent necrosis. Among them, RIPK1/RIPK3/MLKL-dependent necroptosis has received the most attention. Studies have shown that RIPK1/RIPK3/MLKL-dependent necroptosis is present in a variety of injury-related diseases, including myocardial infarction and ischemic stroke. Therefore, inhibiting RIPK1/RIPK3-dependent necroptosis has become an effective way to reduce neuronal cell death in ischemic stroke. It has been reported in the literature that the RIPK1 inhibitor necrostatin-1 (Nec-1) can reduce cerebral ischemia injury and improve neurological function in mice, which is closely related to the inhibition of neuronal necroptosis. However, Nec-1 is only used as a tool drug in animal experiments. At present, there is no clinical drug targeting RIPK1/RIPK3/MLKL for the treatment of ischemic stroke, nor has oxalomalate been used in the treatment of ischemic stroke or neurological disease. Reports in Cell Injury.
发明内容SUMMARY OF THE INVENTION
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。In view of the deficiencies of the prior art, the present invention provides the application of oxalylmalic acid in the preparation of a medicine for treating nerve cell damage.
本发明所述草酰苹果酸的结构式如下式所示：The structural formula of oxalylmalic acid of the present invention is shown in the following formula:
分子式为：C6H3O8；分子量为：272.05。Molecular formula: C 6 H 3 O 8 ; molecular weight: 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。Further, the nerve cells include central nervous system disease-related nerve cells.
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。Further, the central nervous system diseases include traumatic central nervous system injury, brain injury, spinal cord injury, stroke, neurodegenerative disease, Alzheimer's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, Parkinson's disease disease, multiple sclerosis, diabetic neuropathy, spinocerebellar ataxia, fahr's disease, menke's disease, Wilson's disease, cerebral ischemia, prion disease, frontotemporal dementia, dementia with Lewy bodies, cortical basal degeneration, progressive Supranuclear palsy, multiple system atrophy, and hereditary spastic paraplegia.
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。Further, the stroke includes ischemic stroke and/or hemorrhagic stroke.
进一步地，所述缺血性脑卒中包括脑缺血/再灌注损伤。Further, the ischemic stroke includes cerebral ischemia/reperfusion injury.
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。Further, the ischemia/reperfusion injury also includes one or more of myocardial ischemia/reperfusion injury, liver ischemia/reperfusion injury, renal ischemia/reperfusion injury, and lung ischemia/reperfusion injury. kind.
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。Further, the medicine can be prepared into any pharmaceutically acceptable dosage form according to known techniques, such as oral preparations, injections, tablets, capsules, granules, powders, oral liquids or dropping pills, preferably oral administration. agent.
进一步地，所述药物的剂型为口服剂。Further, the dosage form of the medicine is an oral dosage form.
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。Optionally, the administration mode in the application is subcutaneous injection, intravenous injection, intramuscular injection, oral administration or mucosal administration.
可选地，所述应用中的给药方式为口服给药。Optionally, the mode of administration in the application is oral administration.
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。The present invention shows through experiments that oxalylmalic acid can specifically down-regulate the level of phosphorylated MLKL, inhibit nerve cell necroptosis, significantly reduce cerebral ischemic infarction volume and neurobiological score, reduce brain nerve cell death and improve nerve cell function . Therefore, oxalylmalic acid can be applied to prepare a drug for treating ischemia/reperfusion injury.
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。Experiments show that oxalylmalic acid can significantly reduce cerebral ischemia infarction volume and neurobiological score, reduce cerebral nerve cell death and improve nerve cell function, and can be used to prepare cerebral nerve cell damage caused by central nervous system diseases and Neurological disorders including traumatic central nervous system injury, brain injury, spinal cord injury, neurodegenerative disease, Alzheimer's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, Parkinson's disease , multiple sclerosis, diabetic neuropathy, different types of spinocerebellar ataxia, fahr's disease, menke's disease, Wilson's disease, cerebral ischemia, prion disorders, frontotemporal dementia, dementia with Lewy bodies, degeneration of cortical bases, progressive Supranuclear palsy, multiple system atrophy, and hereditary spastic paraplegia.
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。The present invention expands the indications of oxalylmalic acid, and can be applied to ischemia/reperfusion injury; compared with the injection administration method, the present invention can be administered orally, with simple operation, less irritation, and enhanced patient compliance. .
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。Oxalylmalic acid has not been reported for the treatment of stroke. In the present invention, oxalylmalic acid is used for the treatment of ischemic stroke model in rats for the first time, and it is found that oxalylmalic acid can down-regulate the level of phosphorylated MLKL in rat brain tissue, reduce the volume of cerebral infarction in rats, reduce nerve cell damage and improve neurological function. The present invention proves for the first time that oxalylmalic acid can be used for the treatment of ischemic cerebral apoplexy. The invention expands the indication scope of oxalylmalic acid and discovers its new drug action mechanism. Ischemic stroke is a common clinical disease, and oxalylmalic acid has broad application prospects.
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。The inventor's research found that oxalylmalic acid has a new function, which can specifically down-regulate the level of phosphorylated MLKL and inhibit cell necroptosis.
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。In conclusion, the present invention uses oxalylmalic acid for the treatment of cerebral neuropathy, especially the protective effect on ischemic stroke, and can significantly reduce cerebral ischemia/reperfusion injury.
附图说明Description of drawings
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。Figure 1: Administration 15 minutes before surgery, A- rat brain tissue TTC staining and infarct volume determination, B- rat neurological function score.
具体实施方式Detailed ways
动物实验：草酰苹果酸对缺血性脑卒中的保护作用Animal experiment: protective effect of oxalyl malate on ischemic stroke
实施药品：草酰苹果酸购于试剂公司。Implemented drugs: oxalylmalic acid was purchased from Reagent Company.
将草酰苹果酸用生理盐水溶解。Oxalylmalic acid was dissolved in physiological saline.
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。Experimental animals: healthy male SD rats weighing 250-300 g. The experimental animals were raised for a week in an environment with a temperature of 25° C., a relative humidity of 60%, free drinking water, and regular and quantitative conditions, and then the administration group was administered orally according to the experimental requirements.
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。Modeling method: Rat cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion (MCAO). The steps are as follows: (1) Separate the external carotid artery (CCA), separate the left external carotid artery (ECA) and the internal carotid artery (ICA) upward; (2) Use ophthalmic forceps to temporarily clip the ECA and ICA, and ligate the proximal end of the CCA (3) Place a knotted spare silk thread at the distal end of the CCA, cut a small cut at the lower end of the thread, insert the suture into the internal carotid artery, tighten the silk thread, release the arterial clips on the ECA and ICA, and follow the procedure. The ICA sends the suture to the brain; (4) When it encounters resistance, the insertion depth is about 18-20mm from the CCA bifurcation; (5) After 120 minutes of ischemia, the suture is pulled out and the skin is sutured. , the animals were treated after reperfusion for 24h.
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。The model's success evaluation standard adopts Longa's "5-point method" to score the neurological deficit of rat cerebral ischemia injury. 0 points: no symptoms of neurological deficit; 1 point: unable to fully straighten the right forelimb; 2 points: right rotation; 3 points: walking to the right; 4 points: unable to walk spontaneously, loss of consciousness. 1 to 4 are classified as valid models.
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。TTC staining and infarct volume determination in rat brain. After the rats were anesthetized, the brain was quickly taken out, the olfactory bulb and hindbrain were removed, and 4 coronal brain slices, about 2.0 mm thick, were cut from the frontal pole, immediately placed in 1% TTC solution, and incubated at 37°C for 30 min in the dark. Then soak in 10% paraformaldehyde solution for fixation. The infarcted area is white and the non-infarcted area is red. Scanning was performed after each group of brain slices were arranged neatly. ImageJ was then used to measure the infarct area of each brain slice. According to the formula: infarct volume = [(the sum of the infarct area on the front side of each slice + the sum of the infarct area on the back side of each slice)/2]×the thickness of each slice, the same method was used to calculate the whole brain. volume.
实验分组：将实验动物随机分为4组，即：Experimental grouping: The experimental animals were randomly divided into 4 groups, namely:
对照组(control组)：不做任何处理。Control group (control group): no treatment was given.
假手术组(sham组)：分离血管后不插入栓线。Sham operation group (sham group): no suture was inserted after the blood vessels were separated.
缺血/再灌注组(I/R)：脑缺血2h，再灌注24h。Ischemia/reperfusion group (I/R): 2 hours of cerebral ischemia and 24 hours of reperfusion.
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。Oxalylmalic acid + cerebral ischemia/reperfusion group (OMA + I/R): oxalylmalic acid (dosage: 10 mg/kg) was administered by gavage 15 minutes before surgery, followed by 2 hours of cerebral ischemia and 24 hours of reperfusion.
检测指标：大鼠神经功能评分和梗死体积测定。Detection indicators: rat neurological function score and infarct volume measurement.
实验结果Experimental results
草酰苹果酸对大鼠脑梗死体积及神经功能的影响Effects of oxalylmalic acid on cerebral infarction volume and neurological function in rats
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)。As shown in A in Figure 1, the I/R group had obvious white infarction, while the cerebral infarction of the rats in the oxalylmalic acid group before surgery was significantly reduced, and the cerebral ischemia injury was significantly relieved (p<0.01). Panel B, the rats in the cerebral ischemia group (I/R) had obvious neuromotor dysfunction, and oxalylmalic acid could significantly improve the symptoms of neurological deficit (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。However, this patent is not limited to cerebral ischemia/reperfusion injury, because necroptosis also exists in heart, liver and kidney ischemia/reperfusion injury, so the drug is also suitable for the treatment of heart, liver, kidney and lung ischemia/reperfusion injury. reperfusion injury. In addition, the up-regulation of necroptosis in central nervous system diseases leads to brain nerve cell damage and neurological dysfunction, so oxalomalate is also suitable for the treatment of these central nervous system diseases.
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