【摘要】：目的 雖然缺氧誘導(dǎo)因子-la (hypoxia inducible factor-la, HIF-la)在缺血缺氧腦損傷中有大量研究,但是有關(guān)HIF-1α在蛛網(wǎng)膜下腔出血(subarachnoid hemorrhage, SAH)后早期腦損傷(early brain injury, EBI)中的作用仍不清楚,本研究旨在探討HIF-1α在SAH后EBI中的作用及相關(guān)機(jī)制。 方法 采用改良血管內(nèi)穿刺法制作SAH模型。60只雄性SD大鼠隨機(jī)分成以下3組：SAH+2ME2組(SAH+2ME2組)；SAH+二甲亞砜組(SAH+vehicle組)；假手術(shù)+二甲亞砜組(sham+vehicle組)。手術(shù)后24h對各組大鼠血腦屏障通透性、腦組織含水量、細(xì)胞凋亡和皮層HIF-1α、BNIP3和血管內(nèi)皮生長因子(vascular endothelial growth factor, VEGF)表達(dá)水平進(jìn)行檢測；應(yīng)用熒光雙標(biāo)染色法檢測表達(dá)HIF-la的細(xì)胞類型及其與細(xì)胞凋亡是否共同表達(dá)；同時對各組大鼠手術(shù)后24h神經(jīng)功能評分及死亡率進(jìn)行統(tǒng)計(jì)分析。 結(jié)果 與sham+vehicle組比較,SAH后大腦皮層HIF-1α、BNIP3和VEGF的表達(dá)明顯增多,同時細(xì)胞凋亡、血腦屏障通透性、腦水腫及神經(jīng)功能缺損明顯加重(P0.05)；與SAH+vehicle組比較,2ME2干預(yù)后大腦皮層HIF-1α、BNIP3和VEGF的表達(dá)顯著性降低,血腦屏障破壞和腦水腫明顯減輕,同時神經(jīng)功能得到改善(P0.05)；免疫熒光雙標(biāo)染色顯示HIF-1α蛋白主要表達(dá)于神經(jīng)元和TUNEL陽性的細(xì)胞核中。 結(jié)論 我們研究顯示HIF-1α可能通過調(diào)控靶基因BNIP3和VEGF的表達(dá)分別誘導(dǎo)細(xì)胞凋亡和加重血腦屏障破壞和腦水腫,從而在SAH后早期腦損傷中發(fā)揮重要作用。2ME2可通過抑制HIF-1α,進(jìn)而降低BNIP3和VEGF表達(dá),進(jìn)而減輕SAH后細(xì)胞凋亡、血腦屏障破壞和腦水腫,改善大鼠神經(jīng)功能。
[Abstract]:Objective although hypoxia inducible factor (la (hypoxia inducible factor-la, HIF-la) has been studied extensively in ischemic and hypoxic brain injury, HIF-1 偽 is involved in the early brain injury of (early brain injury, after subarachnoid hemorrhage (subarachnoid hemorrhage, SAH). The role of HIF-1 偽 in EBI after SAH is still unclear. Methods 60 male SD rats were randomly divided into three groups: SAH 2ME2 group (SAH 2ME2 group,); SAH dimethyl sulfoxide group, (SAH vehicle group) and sham operation dimethyl sulfoxide group (sham vehicle group), and 60 male SD rats were randomly divided into three groups: SAH 2ME2 group (SAH 2ME2 group,); SAH dimethyl sulfoxide group, (SAH vehicle group) and sham operation dimethyl sulfoxide group (sham vehicle group). The permeability of blood-brain barrier, water content of brain tissue, apoptosis and the expression of HIF-1 偽, BNIP3 and Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) in cortex were detected 24 hours after operation. The cell types of HIF-la expression and their coexpression with apoptosis were detected by fluorescence double labeling staining, and the neurological function score and mortality rate of each group were statistically analyzed 24 hours after operation. Results compared with sham vehicle group, the expression of HIF-1 偽, BNIP3 and VEGF in cerebral cortex after SAH was significantly increased, apoptosis, blood-brain barrier permeability, brain edema and neural function defect were significantly aggravated (P0.05). Compared with SAH vehicle group, the expression of HIF-1 偽, BNIP3 and VEGF in cerebral cortex after 2ME2 intervention was significantly decreased, the blood-brain barrier damage and brain edema were alleviated, and the nerve function was improved (P0.05). Double immunofluorescence staining showed that HIF-1 偽 protein was mainly expressed in neurons and TUNEL positive nuclei. Conclusion our results suggest that HIF-1 偽 may induce apoptosis and aggravate the damage of blood-brain barrier and brain edema by regulating the expression of target gene BNIP3 and VEGF, respectively. 2ME2 can inhibit the expression of HIF-1 偽, then decrease the expression of BNIP3 and VEGF, and then reduce the apoptosis of cells after SAH, the damage of blood-brain barrier and brain edema, and improve the neural function of rats.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R651.15;R743

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