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研究生(外文):CHEN, SU-HUEI
論文名稱(外文):Molecular mechanism underlying disruption of blood-brain barrier caused by epidural compression
指導教授(外文):LIU, PEI-HSIN
外文關鍵詞:epidural compressionprimary somatosensory cortexblood-brain barriertight junctionubiquitin
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我們先前報導,大鼠主要體感覺皮質受硬膜上壓迫會造成短期的腦微血管血腦屏障受損,給予抗氧化劑可避免血腦屏障受損,但其機制仍然未知。In vitro研究顯示,血腦屏障的通透性是由內皮細胞tight junction (TJ) proteins的磷酸化、泛素化及後續的重分布來調控。因此,我們假設主要體感覺皮質受硬膜上壓迫傷害血腦屏障是經由改變TJ proteins磷酸化、泛素化及後續重分布的調節。免疫轉漬實驗結果顯示,主要體感覺皮質受壓迫三天,TJ proteins claudin-5、occludin及JAM-1的表現量不變,但此時血腦屏障受損。給予抗氧化劑增加了claudin-5的表現量,但不增加occludin及JAM-1的表現量。接著,免疫沉降及分餾分析實驗結果顯示,主要體感覺皮質受壓迫三天造成claudin-5 在 cytosol及membrane fraction的磷酸化及泛素化增加。給予抗氧化劑ascorbic acid不但減低了claudin-5的磷酸化及泛素化,也大幅增加了claudin-5 在 membrane fraction的表現量。許多攜帶蛋白例如Epsin1、Eps15及Hrs已確知會負責membrane proteins的endocytosis及intracellular trafficking。因此,我們研究且發現主要體感覺皮質受壓迫造成claudin-5與Epsin1、Eps15及Hrs的作用增加。給予ascorbic acid只減少claudin-5與Epsin1及Eps15的作用,但不減少與Hrs的作用。綜合以上,我們的實驗結果顯示,主要體感覺皮質受硬膜上壓迫傷害血腦屏障是經由claudin-5的磷酸化、泛素化及後續的重分布,ascorbic acid可能可應用在硬膜上壓迫併發血腦屏障受損的治療。
We previously reported that epidural compression of the rat primary somatosensory cortex leads to short-term breakdown of the blood-brain barrier (BBB) of cerebral microvessels, which is prevented by the treatment of antioxidants. However, the underlying mechanism remains unknown. In vitro studies have shown that the permeability of BBB is regulated by the phosphorylation, ubiquitination, and then redistribution of tight junction (TJ) proteins in the endothelial cells. Thus, we hypothesized that epidural compression of the primary somatosensory cortex impairs the BBB through alterations of the regulation of phosphorylation, ubiquitination, and then redistribution of TJ proteins. Immunoblotting demonstrated that the expressions of TJ proteins claudin-5, occludin, and JAM-1 were unaltered at 3 days post-compression when the BBB was disrupted. Treatment of antioxidants increased the expression of claudin-5 but not occludin and JAM-1. Next, immunoprecipitation and fractional analysis showed that 3-day-compression elevated the phosphorylation and ubiquitination of claudin-5 both in the cytosol and membrane fractions. Treatment of ascorbic acid not only reduced the phosphorylation and ubiquitination of claudin-5 but also dramatically increased the expression of claudin-5 in the membrane fraction. A number of carrier proteins such as Epsin1, Eps15, and Hrs are well-known to be responsible for the endocytosis and intracellular trafficking of membrane proteins. Thus, we examined and found that the interaction of claudin-5 with Epsin1, Eps15, and Hrs was increased post-compression. Treatment of ascorbic acid only reduced the interaction of claudin-5 with Epsin1 and Eps15 but not Hrs. Together, these data suggest that epidural compression of the rat primary somatosensory cortex compromises the BBB integrity through phosphorylation, ubiquitination, and redistribution of claudin-5. Ascorbic acid may be used therapeutically to modulate epidural compression complicated with BBB dysfunction.
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