BQ-123对蛛网膜下腔出血大鼠神经功能缺陷的改善作用及其机制

doi:10.13481/j.1671-587x.20160517

吉林大学学报(医学版) ›› 2016, Vol. 42 ›› Issue (05): 925-931.doi: 10.13481/j.1671-587x.20160517

BQ-123对蛛网膜下腔出血大鼠神经功能缺陷的改善作用及其机制

赵雅宁¹, 赵旭², 郭向飞¹, 李建民², 薛承景²

1. 华北理工大学护理与康复学院, 河北唐山 063000;
2. 华北理工大学附属医院神经外科, 河北唐山 063000

收稿日期:2016-03-01 出版日期:2016-09-28 发布日期:2016-09-29
通讯作者: 李建民,教授,硕士研究生导师(Tel:0315-3726234,E-mail:zyning789@126.com) E-mail:zyning789@126.com
作者简介:赵雅宁(1974-),女,河北省唐山市人,教授,医学博士,主要从事神经损伤与神经修复方面的研究。
基金资助:
河北省卫计委重点医学项目资助课题（zd2013087）；河北省唐山市科技局科研基金资助课题（14130220B）

Improvement effect of BQ-123 on nerve function damage after subarachnoid hemorrhage in rats

ZHAO Yaning¹, ZHAO Xu², GUO Xiangfei¹, LI Jianmin², XUE Chengjing²

1. College of Nursing and Rehabilitation, North China University of Science and Technology, Tangshan 063000, China;
2. Department of Neurosurgery, Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China

Received:2016-03-01 Online:2016-09-28 Published:2016-09-29

摘要/Abstract

摘要：

目的：探讨内皮素受体拮抗剂（BQ-123）对蛛网膜下腔出血（SAH）神经功能损伤的影响，阐明其作用机制。方法：120只雄性SD大鼠分为假手术组、SAH模型组、低剂量（50 μg·kg^-1）BQ-123组和高剂量（75 μg·kg^-1）BQ-123组。采用二次注血法制作SAH大鼠模型；HE染色观察各组大鼠海马区神经细胞的形态变化；免疫组织化学法和RT-PCR法检测海马区磷酸化雷帕霉素靶蛋白（mTOR）、自噬相关基因beclin-1和微管相关蛋白1轻链（LC3）-Ⅱ的表达；穿梭箱实验检测各组大鼠学习记忆功能，抓力测定实验评价各时间点各组大鼠前肢拉力情况。结果：与假手术组比较，SAH组大鼠海马区神经细胞结构损伤，神经细胞存活率降低（P<0.05），磷酸化mTOR、beclin-1和LC3-Ⅱ mRNA表达水平升高（P<0.05），大鼠学习记忆功能和拉力值降低（P<0.05）；与SAH组比较，BQ-123组大鼠海马区神经细胞结构损伤减轻，神经细胞存活率升高（P<0.05），磷酸化mTOR mRNA表达水平降低（P<0.05），beclin-1和LC3-Ⅱ mRNA表达水平升高（P<0.05），动物学习记忆功能和拉力值增加（P<0.05）；与低剂量BQ-123组比较，高剂量BQ-123组上述变化更为明显（P<0.05）。结论：BQ-123可显著改善SAH大鼠神经功能缺陷，其机制与调控mTOR-自噬通路信号途径有关。

关键词: 蛛网膜下腔出血, 雷帕霉素靶蛋白, 自噬相关基因, beclin-1, 微管相关蛋白质类

Abstract:

Objective: To study the effect of endothelin receptor antagonist BQ-123 on the nerve function damage after subarachnoid hemorrhage (SAH) in the rats, and to explore the mechanisms. Methods: Total 120 male SD rats were divided into sham group, SAH group, low dose of BQ-123 group (50 μg·kg^-1) and high dose of BQ-123 group(75 μg·kg^-1). The SAH rat models were established by injecting the autologous blood into cisterna magna twice. The morphological changes of hippocampus nerve cells of rat brain tissue were detected with HE staining, and the expressions of mTOR, Beclin-1 and LC3-Ⅱ in the hippocampus of rats were detected with immunohistochemistry and RT-PCR; the shuttle-box experiment was used to evaluate the abilities of learning and memory, and the holding power evaluation was used to evaluate the forelimb pulling force of the rats in various groups at each time point. Results: Compared with sham group, the morphological damages of neurons of the rats in SAH group were increased, the survival rate of neurons of the rats in SAH group was decreased(P<0.05), the expression levels of mTOR mRNA, Beclin-1 mRNA and LC3-Ⅱ mRNA in hippocampus tissue of the rats were increased(P<0.05), and the abtilities of learning and memory and the values of holding power were decreased(P<0.05). Compared with SAH group, the morphological damages of neurons of the rats in BQ-123 groups were decreased, the survival rates of neurons of the rats in BQ-123 groups were increased(P<0.05), the expression levels of mTOR mRNA of rats were decreased(P<0.05), the expression levels of Beclin-1 mRNA and LC3-Ⅱ mRNA in hippocampus tissue were increased(P<0.05), and the abilities of learning and memory and the values of holding power were increased(P<0.05).The changes were more significant in high dose of BQ-123 group compared with low dose of BQ-123 group(P<0.05). Conclusion: BQ-123 can improve the nerve function damage after SAH in the rats, its mechanism may be related to regulating the mTOR/autophagy signaling pathway.

Key words: subarachnoid hemorrhage, mammalian target of rapamycin, autophagy related gene, beclin-1, microtubule-associated proteins

中图分类号:

R651.1

赵雅宁, 赵旭, 郭向飞, 李建民, 薛承景. BQ-123对蛛网膜下腔出血大鼠神经功能缺陷的改善作用及其机制[J]. 吉林大学学报(医学版), 2016, 42(05): 925-931.

ZHAO Yaning, ZHAO Xu, GUO Xiangfei, LI Jianmin, XUE Chengjing. Improvement effect of BQ-123 on nerve function damage after subarachnoid hemorrhage in rats[J]. Journal of Jilin University Medicine Edition, 2016, 42(05): 925-931.

参考文献

[1] Le Roux AA, Wallace MC, Wallace. Outcome and cost of aneurysmal subarachnoid hemorrhage[J]. Neurosurg Clin N Am, 2010, 21(2):235-246.

[2] 王俊华. 蛛网膜下腔出血40例临床治疗效果分析[J]. 西南军医, 2012, 14(1):46-48.

[3] 幸志强, 丁春平, 邱志宏, 等. ETA受体拮抗剂BQ123对心肌梗死局部心肌组织中ET-1和ET受体分布的影响[J]. 中华老年多器官疾病杂志, 2005, 4(3):204-207.

[4] D'SouzaS. Aneurysmal subarachnoid hemorrhage[J]. J Neurosurg Anesthesiol, 2015,27(3):222-240.

[5] Topkoru BC, Altay O, Duris K, et al. Nasal administration of recombinant osteopontin attenuates early brain injury after subarachnoid hemorrhage[J]. Stroke, 2013, 44(11):3189-3194.

[6] 汪文英,崔德荣,江伟.自噬在大脑缺血再灌注损伤中作用的研究进展[J]. 上海交通大学学报:医学版, 2014, 34(2):248-253.

[7] Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress[J]. Mol Cell, 2010, 40(2):310-322.

[8] 马朝晖, 李贵福, 罗望池, 等. 改良"二次枕大池注血法"构建Wistar大鼠蛛网膜下腔出血模型[J]. 中国神经精神疾病杂志, 2012, 38(3):190-192.

[9] 肖遥, 徐善才, 史怀璋. 自噬在蛛网膜下腔出血后早期脑损伤中作用的研究进展[J]. 中国脑血管病杂志, 2013,10(10):553-556.

[10] 杨鹏,赵冬,刘祺,等.氨基胍在大鼠蛛网膜下腔出血后早期脑损伤中的作用[J].医学研究生学报,2015,28(8):794-798.

[11] 姜永生, 叶启发, 陈卫民, 等. BQ123与L-arginine在肝脏缺血再灌注损伤中的作用研究[J]. 肝胆外科杂志, 2001, 9(6):472-473.

[12] Josko J. Cerebral angiogenesis and expression of VEGF after subarachnoid hemorrhage (SAH) in rats[J]. Brain Res, 2003, 981(1/2):58-69.

[13] Itoh S, Sasaki T, Asai A, et al. Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123:change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model[J]. J Neurosurg, 1994, 81(5):759-764.

[14] Ropolo A, Bagnes CI, Molejon MI, et al. Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells[J]. Pancreatology, 2012, 12(1):1-7.

[15] Zhao H, Ji Z, Tang D, et al. Role of autophagy in early brain injury after subarachnoid hemorrhage in rats[J]. Mol Biol Rep, 2013, 40(2):819-827.

[16] 李建柯,刘一之,陈罡,等.Cystatin C对大鼠蛛网膜下腔出血后的自噬的影响[J]. 现代生物医学进展,2013,13(15):2829-2832,2939.

[17] 赵明明, 赵永博, 罗鹏, 等. PI3K/Akt信号通路对神经元机械性损伤诱导的自噬调节作用[J]. 中华神经外科疾病研究杂志, 2012, 11(6):491-494.

[18] Liu L, Fujimoto M, Kawakita F, et al. Anti-vascular endothelial growth factor treatment suppresses early brain injury after subarachnoid hemorrhage in mice[J]. Mol Neurobiol, 2015, 14(4):365.

[19] 庄宗, 赵旭东, 吴颐, 等. PI3K-AKT信号通路在蛛网膜下腔出血后的抗凋亡作用[J]. 医学研究生学报, 2010, 23(6):579-582.

[20] 徐祥. mTOR信号通路在蛛网膜下腔出血后早期脑损伤中的作用及机制研究[D]. 苏州:苏州大学,2014.

[21] 刘琨,许鹏程. 七氟醚预处理对大鼠离体心脏缺血再灌注损伤时自噬的影响及PI3K/Akt信号通路在其中的作用[J]. 中华麻醉学杂志, 2014, 34(4):492-496.

[22] 宫利, 王志, 邢诒刚, 等. 缺血后处理对大鼠脑缺血-再灌注中细胞凋亡的作用及其机制研究[J]. 国际神经病学神经外科学杂志, 2012, 39(3):229-234.

[23] Luo DH, Chen QY, Liu H, et al. The independent, unfavorable prognostic factors endothelin A receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways[J]. J Transl Med, 2013, 11:203.doi:10.1186/1479-5876-11-203.

BQ-123对蛛网膜下腔出血大鼠神经功能缺陷的改善作用及其机制

Improvement effect of BQ-123 on nerve function damage after subarachnoid hemorrhage in rats

RichHTML

PDF (PC)

赞

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 7

Metrics

本文评价

推荐阅读 0

[1]	杨万霞, 苏强, 邢爱华, 张晓延. 饥饿对Beclin-1依赖的Ana-1细胞自噬和凋亡的影响[J]. 吉林大学学报(医学版), 2018, 44(04): 704-708.
[2]	丁显飞, 周学良, 豆萌萌, 李砺锋, 郭丽娜, 王峰, 樊青霞. 哺乳动物雷帕霉素靶蛋白的表达及其与乳腺癌预后关系的Meta分析[J]. 吉林大学学报(医学版), 2016, 42(04): 783-788.
[3]	方芳, 方青, 赵良中, 李强, 陈爽, 张铎, 王立国. CD147通过Beclin-1抑制前列腺癌PC-3细胞自噬[J]. 吉林大学学报(医学版), 2016, 42(01): 15-18.
[4]	何婧, 戚迪, 王导新. 胰岛素通过mTORC2/SGK1途径上调肺泡上皮钠通道α亚基的作用机制[J]. 吉林大学学报(医学版), 2015, 41(04): 716-720.
[5]	吴冰\|康劲松\|王贺元\|晞欣\|邱海洋\|王伟伟\|罗祺. 枕大池二次注血法建立大鼠蛛网膜下腔出血模型及尼莫地平的脑保护作用[J]. J4, 2011, 37(6): 1153-1156.
[6]	刘玉和，于春艳，王皓，孙连坤. Vk3对宫颈癌Hela细胞mTOR信号转导蛋白基因表达的影响[J]. J4, 2009, 35(2): 267-270.
[7]	徐宁，王宏磊，罗祺，罗毅男，王长坤. 蛛网膜下腔出血506例临床分析[J]. J4, 2004, 30(1): 138-140.