背景:癡呆患者中約30-40%的患者存在著血管性癡呆（Vascular Dementia,Va D）的病理表現(xiàn)。其中,由于小血管病變造成的慢性腦低灌注引起的皮層下缺血性血管性癡呆（Subcortical ischemic vascular dementia,SIVD）是血管性癡呆的一種常見亞型。SIVD多見于高血壓、動脈硬化的患者及老年人。SIVD的腦白質(zhì)病理改變包括少突膠質(zhì)細(xì)胞損傷、脫髓鞘和腦白質(zhì)稀疏化等,進(jìn)而會導(dǎo)致進(jìn)行性的認(rèn)知功能障礙,嚴(yán)重影響患者的生活質(zhì)量。雖然目前臨床上利用膽堿酯酶抑制劑或血管擴(kuò)張藥可以緩解部分癥狀,但尚無針對性的能夠減緩疾病進(jìn)程的藥物。因此,開發(fā)出具有神經(jīng)保護(hù)作用的可持續(xù)治療藥物迫在眉睫。腦白質(zhì)主要是由少突膠質(zhì)細(xì)胞構(gòu)成的髓鞘包裹神經(jīng)元軸突而形成。并且,髓鞘的完整性是維持神經(jīng)元功能、神經(jīng)沖動的跳躍式傳導(dǎo)以及正常認(rèn)知功能的必要條件。研究發(fā)現(xiàn),慢性低灌注腦白質(zhì)損傷區(qū)域會發(fā)生髓鞘堿性蛋白丟失、少突膠質(zhì)細(xì)胞凋亡、髓鞘脫失。雖然在某些脫髓鞘損傷中,少突膠質(zhì)細(xì)胞前體細(xì)胞（OPCs）會增殖并遷移到目標(biāo)軸突,并分化成成熟的少突膠質(zhì)細(xì)胞形成髓鞘,但是在慢性低灌注引起的腦白質(zhì)損傷中... 

【文章來源】：浙江大學(xué)浙江省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：123 頁

【學(xué)位級別】：博士

【文章目錄】：
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


【參考文獻(xiàn)】：
期刊論文
[1]AATYK is a Novel Regulator of Oligodendrocyte Differentiation and Myelination[J]. Chunxia Jiang,Wanqing Yang,Zhihong Fan,Peng Teng,Ruyi Mei,Junlin Yang,Aifen Yang,Mengsheng Qiu,Xiaofeng Zhao.  Neuroscience Bulletin. 2018(03)
[2]Myt1L Promotes Differentiation of Oligodendrocyte Precursor Cells and is Necessary for Remyelination After Lysolecithin-Induced Demyelination[J]. Yanqing Shi,Qi Shao,Zhenghao Li,Ginez A.Gonzalez,Fengfeng Lu,Dan Wang,Yingyan Pu,Aijun Huang,Chao Zhao,Cheng He,Li Cao.  Neuroscience Bulletin. 2018(02)
[3]Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion[J]. Jing Ma,Shu-hong Bo,Xiao-tong Lu,A-jing Xu,Jian Zhang.  Neural Regeneration Research. 2016(09)



本文編號：3370224