c-Jun氨基末端激酶介导的FOXO3a核转位在缺氧缺血性脑损伤新生大鼠神经元凋亡中的作用

发布时间：2018-12-15 01:02

【摘要】：目的探讨抑制c-Jun氨基末端激酶(JNK)/核转录因子FOXO3a信号通路对缺氧缺血性脑损伤(HIBD)新生大鼠神经元凋亡的保护作用机制。方法将64只7日龄Sprague-Dawley大鼠随机分为假手术组、缺氧缺血(HI)组、二甲基亚砜(DMSO)溶剂组和JNK特异性抑制剂AS601245干预组(JNK抑制剂组)。各组分别在建模后24 h处死动物取大脑皮层,应用Western blot法定量检测JNK、p-JNK、FOXO3a、胞核FOXO3a、胞浆FOXO3a,以及促凋亡蛋白Bim及CC3的表达水平;应用TUNEL染色法检测神经细胞凋亡情况。结果与假手术组相比,HI后24 h,p-JNK蛋白水平增高(P0.01);胞核FOXO3a蛋白水平增高,胞浆FOXO3a蛋白水平降低(P0.01);Bim及CC3表达水平增高(P0.01)。与HI组及DMSO溶剂组相比,JNK抑制剂组p-JNK蛋白水平降低(P0.01);胞核FOXO3a蛋白水平降低,胞浆FOXO3a蛋白水平增高(P0.01);Bim及CC3表达水平降低(P0.01)。JNK抑制剂组的TUNEL染色阳性细胞表达较HI组及DMSO溶剂组减少(P0.01)。结论新生大鼠HIBD时,JNK发生磷酸化,活性增高;抑制JNK活性可抑制FOXO3a核转位,下调促凋亡蛋白Bim及CC3表达,减少神经细胞凋亡。
[Abstract]:Objective to investigate the protective mechanism of inhibition of c-Jun amino-terminal kinase (JNK) / nuclear transcription factor FOXO3a signaling pathway on neuronal apoptosis in neonatal (HIBD) rats with hypoxic-ischemic brain injury. Methods Sixty-four 7-day-old Sprague-Dawley rats were randomly divided into sham-operation group, hypoxic-ischemic (HI) group, dimethyl sulfoxide (DMSO) solvent group and AS601245 intervention group (JNK inhibitor group). All the animals were killed 24 hours after modeling. The expression levels of FOXO3a, cytoplasm FOXO3a, and apoptosis-promoting proteins Bim and CC3 in the nucleus of JNK,p-JNK,FOXO3a, were detected by Western blot assay. Apoptosis of nerve cells was detected by TUNEL staining. Results compared with the sham-operated group, the level of p-JNK protein increased at 24 h after HI (P0.01), the level of nuclear FOXO3a protein increased, and the level of cytoplasmic FOXO3a protein decreased (P0.01); Bim and CC3 expression level increased (P0.01). Compared with the HI group and the DMSO solvent group, the p-JNK protein level in the JNK inhibitor group decreased (P0.01), the FOXO3a protein level in the nucleus decreased and the FOXO3a protein level in the cytoplasm increased (P0.01). The expression of Bim and CC3 decreased (P0.01). JNK inhibitor group, compared with HI group and DMSO group (P0.01). Conclusion during HIBD, JNK is phosphorylated and its activity is increased, inhibition of JNK activity can inhibit FOXO3a nuclear translocation, down-regulate the expression of Bim and CC3, and decrease neuronal apoptosis.
【作者单位】：四川大学华西第二医院儿科/出生缺陷与相关妇儿疾病教育部重点实验室;
【基金】：国家自然科学基金(81000262) 四川省卫生和计划生育委员会科研课题(16PJ240);四川省卫生和计划生育委员会资助项目(140045)
【分类号】：R742

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