2,3-二羟基苯甲酸十四烷基酯对慢性脑低灌注引起的脑白质损伤的保护作用研究

发布时间：2021-08-29 07:50

　　背景:痴呆患者中约30-40%的患者存在着血管性痴呆（Vascular Dementia,Va D）的病理表现。其中,由于小血管病变造成的慢性脑低灌注引起的皮层下缺血性血管性痴呆（Subcortical ischemic vascular dementia,SIVD）是血管性痴呆的一种常见亚型。SIVD多见于高血压、动脉硬化的患者及老年人。SIVD的脑白质病理改变包括少突胶质细胞损伤、脱髓鞘和脑白质稀疏化等,进而会导致进行性的认知功能障碍,严重影响患者的生活质量。虽然目前临床上利用胆碱酯酶抑制剂或血管扩张药可以缓解部分症状,但尚无针对性的能够减缓疾病进程的药物。因此,开发出具有神经保护作用的可持续治疗药物迫在眉睫。脑白质主要是由少突胶质细胞构成的髓鞘包裹神经元轴突而形成。并且,髓鞘的完整性是维持神经元功能、神经冲动的跳跃式传导以及正常认知功能的必要条件。研究发现,慢性低灌注脑白质损伤区域会发生髓鞘碱性蛋白丢失、少突胶质细胞凋亡、髓鞘脱失。虽然在某些脱髓鞘损伤中,少突胶质细胞前体细胞（OPCs）会增殖并迁移到目标轴突,并分化成成熟的少突胶质细胞形成髓鞘,但是在慢性低灌注引起的脑白质损伤中... 

【文章来源】：浙江大学浙江省 211工程院校 985工程院校 教育部直属院校

【文章页数】：123 页

【学位级别】：博士

【文章目录】：
Dedication
Acknowledgement
Abstract
中文摘要
Abbreviations
1 Introduction
2 Materials
    2.1 Experimental animals
    2.2 Instruments
    2.3 Solutions preparation
3 Methods
    3.1 Groups of Animals
    3.2 rUCCAO procedure
    3.3 Cerebral blood flow(CBF)measurement
    3.4 Drugs administration
    3.5 Novel object recognition task
    3.6 Morris water maze test
    3.7 Immunohistochemistry
    3.8 Electron microscopy
    3.9 Chronic toxicity study
        3.9.1 The biochemical and hematological assessment
        3.9.2 H&E procedure
    3.10 Computational study
    3.11 Oligodendrocyte culture and oxygen glucose deprivation/reperfusion
    3.12 Primary oligodendrocyte culture
        3.12.1 Dissection of rat cortices
        3.12.2 Tissue lysis
        3.12.3 Oligodendrocyte culture and treatment
    3.13 Apoptosis assay
    3.14 Protein extraction
    3.15 Western blotting analysis
        3.15.1 Gel preparation,samples loading and electrophoresis
        3.15.2 Transferring(blotting),blocking,antibodies incubation and detection
    3.16 Plasmids and transfections
    3.17 Statistical analysis
4 Results
    4.1 The CBF after rUCCAO declined in the cerebral hemisphere ipsilateral to the arterial occlusion
    4.2 ABG-001 alleviates myelin sheath and oligodendrocyte damage after rUCCAO
    4.3 ABG-001 alleviates demyelination and axonal damage after rUCCAO
    4.4 ABG-001 relieves cognitive impairments after rUCCAO
    4.5 ABG-001 alleviates oligodendrocyte damage during the early response to cerebral hypoperfusion
    4.6 ABG-001 alleviated oligodendrocyte damage induced by OGD in cultured Oli-neu cells and primary oligodendrocytes
    4.7 ABG-001 has binding affinity for IGF-1R
    4.8 The3D structure of ABG-001 closely aligned with the co-crystallized ligand of IGF-1R,FUC
    4.9 ABG-001 has low affinity for Trk A
    4.10 Protective effect of ABG-001 against oligodendrocyte damage was mainly mediated by stimulation of IGF-1R in differentiated Oli-neu cells
    4.11 Protective effect of ABG-001 against oligodendrocyte damage in vivo was mediated by activation of IGF-1R
    4.12 Chronic treatment with ABG-001 has no effect on body weight or toxic effects on liver or kidney tissues
    4.13 ABG-001 has no effect on biochemical parameters
    4.14 ABG-001 has no effect on hematological parameters
Discussion
Conclusion
References
Review Pharmacological interventions of ischemic white matter damage
    References
Publications


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期刊论文
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