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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/63313


    題名: 新穎缺血性腦損傷的神經保護策略：以小鼠模型為研究對象，針對急性衰老和急性高血糖的治療方針
    Novel Neuroprotective Strategies Against Ischemic Stroke: Targeting Acute Senescence and Acute Hyperglycemia in a Mouse Model
    作者: 盧冠蓉
    LU, KUAN-JUNG
    貢獻者: 醫學科學研究所博士班
    謝政穎
    關鍵詞: 急性衰老;急性高血糖;小鼠中風模型;缺血性腦損傷
    acute senescence;hyperglycemia;acute ischemic stroke;MCAO mouse model
    日期: 2023-06-30
    上傳時間: 2023-12-11 14:21:10 (UTC+8)
    摘要: 急性缺血性中風（AIS）是需要有效介入治療。本研究旨在探討在AIS疾病中利用清除衰老細胞和過度表現乙醛?化?1（GLO1）的潛在治療效益。第一部分主要為探討急性神經細胞衰老在AIS發病過程中的機制探討。我們利用一種新型的lenti-INK-ATTAC病毒載體在局部清除衰老腦細胞。我們的研究發現，中大腦動脈栓塞（MCAO）手術後，星形細胞和腦內皮細胞（CECs）出現急性衰老現象。在缺氧以及葡萄糖剝奪培養的的星形細胞和CECs中觀察到p16INK4a的上調以及基質金屬蛋白?-3、白介素-1α和-6等衰老相關分泌表型（SASP）因子的上調。抗衰老藥物ABT-263的治療防止了缺血性腦損傷對大腦葡萄糖利用的損害，顯著改善了神經嚴重程度評分(NSS scores)、轉動槳表現(Rota-Rod)、運動活動和體重損失。ABT-263的治療減少了MCAO小鼠中星形細胞和CECs的衰老。此外，經由注射lenti-INK-ATTAC病毒在損傷的大腦中, 可局部清除衰老細胞產生了神經保護作用，保護了急性缺血性腦損傷的小鼠。MCAO小鼠的腦組織中的SASP因子含量和p16INK4a的mRNA水平在lenti-INK-ATTAC病毒感染後顯著降低。上述結果顯著證明，局部清除衰老腦細胞是AIS的潛在治療效果，同時也證明神經細胞衰老與AIS發病機制之間的相關性。
    第二部分著眼於缺血腦部壓力誘發高血糖（SIH）對AIS結果的不良影響。本研究在探討乙醛?化?1（GLO1）的過度表現對急性高血糖加重的缺血性腦損傷的治療評估。經由AAV(adeno-virus)介入所引導的GLO1過度表達，可以顯著減少大腦中的梗死體積和腦水腫程度。然而，在單純的MCAO小鼠中，這並沒有改善神經功能恢復。有趣的是，GLO1過度表達可顯著改善急性高血糖MCAO小鼠的神經功能恢復，但對正常血糖小鼠則無明顯效果。此外，在甲基乙二醛Methylglyoxal (MG) 刺激的細胞中，GLO1過度表達減少了MG修飾蛋白、內質網應激形成以及caspase3/7活化。在急性高血糖MCAO小鼠的損傷皮層中，突觸可塑性的降低和小膠細胞活化的減輕也得到緩解。手術後使用GLO1刺激劑ketotifen進一步減輕了MCAO小鼠急性高血糖的神經功能缺陷和缺血性腦損傷。綜合以上所述，此篇論文實驗結果顯示，清除衰老腦細胞或是提高GLO1的表達在AIS治療中具有潛在的治療效果。未來的研究應該探討這些治療方式的協同效應，並將其應用於臨床研究中，期許在未來能夠改善AIS患者的癒後結果。
    Acute ischemic stroke (AIS) is a condition that requires effective therapeutic interventions. In this study, we aimed to investigate the potential benefits of combining senolytic treatment and glyoxalase 1 (GLO1) overexpression in the context of AIS.
    The first part of study focused on the role of acute senescence of neuronal cells in the pathogenesis of AIS. We utilized a novel lenti-INK-ATTAC viral vector to eliminate senescent brain cells locally. Our findings demonstrated that acute senescence was induced in astrocytes and cerebral endothelial cells (CECs) following middle cerebral artery occlusion (MCAO) surgery. Senescence-associated secretory phenotype (SASP) factors, including matrix metalloproteinase-3, interleukin-1 alpha, and -6, were upregulated in oxygen-glucose deprivation-treated astrocytes and CECs. Treatment with the senolytic ABT-263 prevented brain impairment and improved neurological outcomes in mice. Furthermore, localized clearance of senescent cells through lenti-INK-ATTAC viral injection exerted neuroprotective effects and mitigated ischemic brain injury in mice. These results suggest that the removal of senescent brain cells may represent a potential therapy for AIS.
    The second part focused on stress-induced hyperglycemia (SIH) and its detrimental effects on AIS outcomes. Glyoxalase 1 (GLO1), a detoxifying enzyme, was investigated for its therapeutic potential in alleviating SIH-aggravated ischemic brain injury. Overexpression of GLO1 via AAV-mediated infection reduced infarct volume and edema level. However, it did not improve neurofunctional recovery in mice with MCAO alone. Interestingly, GLO1 overexpression significantly enhanced neurofunctional recovery in MCAO mice with acute hyperglycemia but not in normoglycemic mice. In addition, GLO1 overexpression attenuated the induction of MG-modified proteins, ER stress formation, and caspase3/7 activation in MG-treated cells. Reductions in synaptic plasticity and microglial activation were also mitigated in the injured cortex of MCAO mice with acute hyperglycemia. Treatment with ketotifen, a GLO1 stimulator, after surgery further alleviated neurofunctional deficits and ischemic brain damage in MCAO mice with acute hyperglycemia.
    Overall, the combined findings suggest that the localized clearance of senescent brain cells and the upregulation of GLO1 have potential therapeutic implications for AIS. Future studies should investigate the synergistic effects of these interventions and their translation into clinical applications for improved outcomes in patients with AIS.
    描述: 博士
    指導教授:謝政穎
    委員:許準榕
    委員:顏茂雄
    委員:沈明毅
    委員:黃德富
    資料類型: thesis
    顯示於類別:[醫學科學研究所] 博碩士論文

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