脑苷肌肽在大鼠脑出血后的神经保护效应及机制研究
发布时间：2018-12-21 11:00
【摘要】：脑出血破入脑室的高发病率、高死亡率和高致残率给全球带来沉重的经济负担。然而迄今为止,针对脑出血外科手术治疗及血压管理的几项临床实验均为阴性结果,1000余种神经保护药物的临床转化也均宣告失败,脑出血临床治疗尚且缺乏有效的治疗方法。目前基础研究也多集中研究单纯脑出血,针对脑出血破入脑室这一严重脑出血亚型的研究尚为一片空白,此外面对脑出血破入脑室后复杂的病理损伤机制,目前单一靶点、单一分子通路的神经保护药物研究恐难有成效。脑苷肌肽,一种复合型多靶点神经保护药物,具有高度血脑屏障通透性,其主要成分为多肽、多种神经节苷脂、游离氨基酸、次黄嘌呤等,临床应用于治疗中枢神经及周围神经损伤疾病,基础研究也已证实其在阿兹海默病、创伤性脑损伤、视网膜变性等多种动物模型中具有神经保护作用,但其在出血性卒中的神经保护效应及机制目前仍不清楚。本实验第一部分建立大鼠脑出血破入脑室模型,研究不同剂量脑苷肌肽对大鼠脑出血破入脑室后神经功能恢复的影响;第二部分,研究脑苷肌肽在脑出血破入脑室后神经保护效应的可能作用机制和潜在靶点,为脑出血破入脑室的临床治疗提供新的思路及方法。一、Ⅳ型胶原酶诱导大鼠脑出血并破入脑室模型的建立及脑苷肌肽最适剂量探索目的通过对传统大鼠脑出血模型进行改良,建立大鼠脑出血破入脑室标准化模型,运用行为学评估手段,评估多靶点复合神经保护药物脑苷肌肽不同剂量对大鼠脑出血后神经功能恢复的影响。方法参照Rosenberg等提出的方法,并在本实验室前期研究工作基础上,调整Ⅳ型胶原酶注射坐标及剂量,将0.2U Ⅳ型胶原酶注入大鼠右侧脑基底节区(前囟旁3毫米、后2毫米、深6毫米),3天后灌注取脑观察血肿破入脑室情况。将大鼠随机分为假手术组(Sham组),模型组(ICH组),模型+脑苷肌肽高剂量治疗干预组(ICH+4ml/kg CEGI),模型+脑苷肌肽低剂量治疗干预组(ICH+1ml/kg CEGI),模型+神经节苷脂治疗干预组(ICH+GM1),术后3天、7天、14天运用改良加西亚量表,转角试验两种方法评估大鼠神经功能恢复情况。结果1、术后3天可见血肿形成且破入侧脑室,脑室扩张;2、神经节苷脂与4ml/kg脑苷肌肽能够显著改善大鼠脑出血预后,促进大鼠神经功能恢复;3、低剂量脑苷肌肽干预组大鼠神经功能缺损与模型组无明显差异。结论此模型建立方法效果确切,成功模拟了临床脑出血并破入脑室这一严重脑出血亚型,此外,行为学结果提示,4ml/kg脑苷肌肽能够改善大鼠脑出血预后,其机制需要进一步探究。二、脑苷肌肽治疗大鼠脑出血并破入脑室的机制研究目的在第一部分研究中,我们发现大鼠脑出血破入脑室在经过4ml/kg脑苷肌肽连续干预14天后,其神经功能缺损得到显著改善,新近文献表明脑苷肌肽的几项主要组成成分具有抗氧化、促进轴突再生、再髓鞘化等作用,因此,本实验拟探究脑苷肌肽治疗大鼠脑出血破入脑室的可能机制。方法将实验动物随机分成假手术组(Sham组),模型组(ICH组),模型+脑苷肌肽治疗干预组(ICH+4ml/kg CEGI)。术后2小时首次腹腔注射给药,连续给药14天。分别在术后3天、7天、14天运用小动物7.0T核磁共振成像动态观察血肿、侧脑室体积变化。术后7天、14天运用激光共聚焦、透射电子显微镜等技术手段动态观察脑出血后血肿周围及皮层白质损伤。结果1、脑苷肌肽治疗干预组术后第14天血肿吸收率较模型组显著提高;2、脑苷肌肽治疗干预组术后第14天侧脑室体积扩张程度显著减缓,远期重度脑积水发生率显著下降;3、脑苷肌肽治疗干预组术后7天、14天皮层髓鞘碱性蛋白表达量显著增加,血肿周围白质纤维束超微结构损伤明显改善。结论大鼠脑出血破入脑室,经过脑苷肌肽干预后,出血后血肿周围及皮层白质损伤能够显著缓解,血肿吸收得到促进,侧脑室体积扩张程度减缓,远期重度脑积水发生率降低,神经功能恢复得到促进,脑苷肌肽具有显着的神经保护作用,因此可作为脑出血破入脑室临床治疗的新方法。
[Abstract]:The high morbidity, high mortality and high disability rate of the cerebral hemorrhage to the ventricles have brought a heavy economic burden to the world. So far, the clinical conversion of more than 1000 kinds of neuroprotective drugs has failed due to the negative result of several clinical trials for the surgical treatment of cerebral hemorrhage and the management of blood pressure, and the clinical treatment of the cerebral hemorrhage is still short and the effective treatment method is not available. The present basic research also focuses on the study of the simple cerebral hemorrhage, and the study on the cerebral hemorrhage of the cerebral hemorrhage is a blank, and in addition to the complicated pathological damage mechanism after the cerebral hemorrhage is broken into the ventricle, the single target point is not present at present. The study of the neuroprotective drug of a single molecular pathway may be difficult to achieve. the brain papillary muscle peptide, a compound multi-target nerve protection medicine, has the high blood-brain barrier permeability, the main component of the brain-derived muscle peptide is a polypeptide, a plurality of ganglionic fat, a free amino acid, a secondary flavopterin and the like, and is clinically applied to the treatment of the central nervous system and the peripheral nerve injury disease, The underlying studies have also been shown to have neuroprotective effects in various animal models, such as Alzheimer's disease, traumatic brain injury, and retinal degeneration, but their neuroprotective effects and mechanisms in hemorrhagic stroke are still unclear. In the first part of this experiment, the cerebral hemorrhage of rats was established to break into the ventricular model, and the effect of different doses of the brain myostatin on the recovery of the neurological function after the cerebral hemorrhage of the rat was broken into the ventricle was studied. The second part, To study the possible mechanism and potential target of the neuroprotective effect of the brain-derived myopeptide in the post-cerebral hemorrhage of the cerebral hemorrhage, and to provide a new thought and method for the clinical treatment of the cerebral hemorrhage. one, type 鈪，
本文编号：2388818
[Abstract]:The high morbidity, high mortality and high disability rate of the cerebral hemorrhage to the ventricles have brought a heavy economic burden to the world. So far, the clinical conversion of more than 1000 kinds of neuroprotective drugs has failed due to the negative result of several clinical trials for the surgical treatment of cerebral hemorrhage and the management of blood pressure, and the clinical treatment of the cerebral hemorrhage is still short and the effective treatment method is not available. The present basic research also focuses on the study of the simple cerebral hemorrhage, and the study on the cerebral hemorrhage of the cerebral hemorrhage is a blank, and in addition to the complicated pathological damage mechanism after the cerebral hemorrhage is broken into the ventricle, the single target point is not present at present. The study of the neuroprotective drug of a single molecular pathway may be difficult to achieve. the brain papillary muscle peptide, a compound multi-target nerve protection medicine, has the high blood-brain barrier permeability, the main component of the brain-derived muscle peptide is a polypeptide, a plurality of ganglionic fat, a free amino acid, a secondary flavopterin and the like, and is clinically applied to the treatment of the central nervous system and the peripheral nerve injury disease, The underlying studies have also been shown to have neuroprotective effects in various animal models, such as Alzheimer's disease, traumatic brain injury, and retinal degeneration, but their neuroprotective effects and mechanisms in hemorrhagic stroke are still unclear. In the first part of this experiment, the cerebral hemorrhage of rats was established to break into the ventricular model, and the effect of different doses of the brain myostatin on the recovery of the neurological function after the cerebral hemorrhage of the rat was broken into the ventricle was studied. The second part, To study the possible mechanism and potential target of the neuroprotective effect of the brain-derived myopeptide in the post-cerebral hemorrhage of the cerebral hemorrhage, and to provide a new thought and method for the clinical treatment of the cerebral hemorrhage. one, type 鈪，
本文编号：2388818
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