«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《国际心血管病杂志》[ISSN:1006-6977/CN:61-1281/TN]

期数:

2020年02期

页码:

103-108

栏目:

基础研究

出版日期:

2020-03-29

文章信息/Info

Title:

Deep hypothermic circulatory arrest impairs cognitive function by inhibiting Akt signaling pathway in rats

作者:

刘金铎 高诗仑 时将 师恩祎 蒋璇 谷天祥

110122 沈阳,中国医科大学附属一院心脏外科

Author(s):

LIU Jinduo;  GAO Shilun;  SHI Jiang;  SHI Enyi;  JIANG Xuan;  GU Tianxiang

Department of Cardiac Surgery, The First Hospital of China Medical University, Liaoning 110122, China

关键词:

深低温停循环;  认知功能;  凋亡;  丝氨酸/苏氨酸蛋白激酶

Keywords:

Deep hypothermic circulatory arrest;  Cognitive function;  Apoptosis;  Serine/threonine protein kinase

分类号:

-

DOI:

10.3969/j.issn.1673-6583.2020.02.010

文献标识码:

-

摘要:

目的:探究大鼠深低温停循环(DHCA)术后脑损伤情况及作用机制。方法:建立大鼠深低温停循环模型,16只SD大鼠随机分成假手术组和DHCA组。再灌注4 h后Western blot法检测海马组织丝氨酸/苏氨酸激酶(Akt)、磷酸化丝氨酸/苏氨酸激酶(p-Akt)、B淋巴细胞瘤/白血病-2(Bcl-2)、Bcl-2相关X蛋白(Bax)和活化胱天蛋白酸-3(cleaved caspase-3)表达水平。HE染色及尼氏染色评估术后第7天海马CA1区神经元损伤情况。Morris水迷宫评价大鼠学习记忆、空间感知及运动能力。结果:与假手术组相比,DHCA组海马CA1区p-Akt、Bcl-2的蛋白表达水平降低,Bax、cleaved caspase-3的蛋白表达水平升高(P均<0.05),两组Akt的蛋白表达水平无统计学差异。DHCA组病理评分明显高于假手术组,正常神经细胞数量均明显低于假手术组,大鼠逃避潜伏期、跨越原平台次数及运动速度均明显弱于假手术组(P均<0.05)。结论:DHCA通过抑制Akt信号通路介导神经细胞凋亡,对大鼠认知等功能造成损伤。

Abstract:

Objective:To observe the brain injury after deep hypothermic circulatory arrest(DHCA)in rats, and to investigate the mechanism of it.Methods:A rat model of DHCA was established. Sixteen Sprague-Dawley rats were randomly divided into sham operation group(Sham group)and DHCA group.The expression of serine/threonine protein kinase(Akt), phosphorylation Akt(p-Akt), B-cell lymphoma/leukemia-2(Bcl-2), Bcl-2 associated X protein(bax)and cleaved cysteine aspartyl protease-3(caspase-3)in hippocampus were detected by western blot analysis four hours after reperfusion. Hematoxylin-eosin(HE)staining and Nissl staining were used to evaluate the neuronal damage in hippocampal CA-1 sector on the 7th day after operation. Morris water maze was used to evaluate the learning, memorizing, space perception and exercise capacity in rats.Results:Compared with the Sham group, the expression of p-Akt and Bcl-2 in the hippocampus CA-1 sector of DHCA group was lower, while the expression of Bax and cleaved-caspase 3 was increased(all P<0.05). And there was no statistically difference between the two groups in terms of the expression of Akt. The pathological score in the DHCA group was higher than that in the Sham group, while the number of survival neurons in the DHCA group was fewer than that in the Sham group. Comparing with the Sham group, in the DHCA group the escape latency was longer, and the times of crossing platform were shorter with slower movement(all P<0.05).Conclusions:DHCA can mediate neuronal apoptosis by inhibiting Akt signaling pathway, and impair cognitive function in rats as result.

参考文献/References

[ 1 ] Griepp RB, Stinson EB, Hollingsworth JF, et al. Prosthetic replacement of the aortic arch[J]. J Thorac Cardiovasc Surg, 1975, 70(6):1051-1063.
[ 2 ] Kaneko T, Aranki SF, Neely RC, et al. Is there a need for adjunct cerebral protection in conjunction with deep hypothermic circulatory arrest during noncomplex hemiarch surgery?[J]. J Thorac Cardiovasc Surg, 2014, 148(6):2911-2917.
[ 3 ] Ergin MA, Uysal S, Reich DL, et al. Temporary neurological dysfunction after deep hypothermic circulatory arrest: a clinical marker of long-term functional deficit[J]. Ann Thorac Surg, 1999, 67(6):1887-1890.
[ 4 ] Harrington DK, Bonser M, Moss A, et al. Neuropsychometric outcome following aortic arch surgery: a prospective randomized trial of retrograde cerebral perfusion[J]. J Thorac Cardiovasc Surg, 2003, 126(3):638-644.
[ 5 ] Jiang X, Gu T, Liu Y, et al. A novel augmented venous-drainage model of cardiopulmonary bypass for deep hypothermic circulatory arrest without blood priming[J]. Perfusion, 2018, 33(4):297-302.
[ 6 ] Morris RG. Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5[J]. J Neurosci, 1989, 9(9):3040-3057.
[ 7 ] Shen L, Wang J, Liu K, et al. Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest[J]. Neurochem Res, 2011, 36(8):1501-1511.
[ 8 ] Zhang X, Xue X, Zhao J, et al. Diosgenin attenuates the brain injury induced by transient focal cerebral ischemia-reperfusion in rats[J]. Steroids, 2016, 113:103-112.
[ 9 ] Li P, Gu T, Wang C, et al. Neuregulin 1 attenuates neuronal apoptosis induced by deep hypothermic circulatory arrest through ErbB4 signaling in rats[J]. J Cardiovasc Pharmacol, 2015, 66(6):551-557.
[10] Colicos MA, Dash PK. Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits[J]. Brain Res, 1996, 739(1/2):120-131.
[11] Tsujimoto Y. Bcl-2 family of proteins: Life-or-death Switch in mitochondria[J]. Biosci Rep, 2002, 22(1):47-58.
[12] Murphy KM, Streips UN, Lock RB. Bcl-2 inhibits a Fas-induced conformational change in the Bax N terminus and Bax mitochondrial translocation[J]. J Biol Chem, 2000, 275(23):17225-17228.
[13] Wei R, Zhang R, Xie Y, et al. Hydrogen suppresses hypoxia/Reoxygenation-Induced cell death in hippocampal neurons through reducing oxidative stress[J]. Cell Physiol Biochem, 2015, 36(2):585-598.
[14] Ji HJ, Hu JF, Wang YH, et al. Osthole improves chronic cerebral hypoperfusion induced cognitive deficits and neuronal damage in hippocampus[J]. Eur J Pharmacol, 2010, 636(1/3):96-101.
[15] McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease[J]. Cold Spring Harb Perspect Biol, 2015, 7(4):a026716.
[16] Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics[J]. Brain Res Rev, 2007, 54(1):34-66.
[17] Sugawara T, Fujimura M, Noshita N, et al. Neuronal death/survival signaling pathways in cerebral ischemia[J]. NeuroRx, 2004, 1(1):17-25.
[18] Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival[J]. J Cell Mol Med, 2005, 9(1):59-71.
[19] Beaulieu JM, Sotnikova TD, Yao WD, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade[J]. Proc Natl Acad Sci U S A, 2004, 101(14):5099-5104.
[20] Kim SY, Yoo SJ, Ronnett GV, et al. Odorant stimulation promotes survival of rodent olfactory receptor neurons via PI3K/Akt activation and Bcl-2 expression[J]. Mol Cells, 2015, 38(6):535-539.
[21] Liang K, Ye Y, Wang Y, et al. Formononetin mediates neuroprotection against cerebral ischemia/reperfusion in rats via downregulation of the Bax/Bcl-2 ratio and upregulation PI3K/Akt signaling pathway[J]. J Neurol Sci, 2014, 344(1/2):100-104.
[22] Zhang M, Yan H, Li S, et al. Rosmarinic acid protects rat hippocampal neurons from cerebral ischemia/reperfusion injury via the Akt/JNK3/caspase-3 signaling pathway[J]. Brain Res, 2017, 1657:9-15.
[23] Chu J, Lauretti E, Praticò D. Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer's disease[J]. Mol Psychiatry, 2017, 22(7):1002-1008.
[24] Zahedi M, Hojjati MR, Fathpour H, et al. Effect of rheum ribes hydro-alcoholic extract on memory impairments in rat model of alzheimer's disease[J]. Iran J Pharm Res, 2015, 14(4):1197-1206.

备注/Memo

备注/Memo:

基金项目:国家自然科学基金(81770467)
作者单位:110122 沈阳,中国医科大学附属一院心脏外科
通信作者:谷天祥,E-mail:cmugtx@sina.com

常用功能

更新日期/Last Update: 2020-03-30